Introduction

Bone remodelling is a tightly coupled lifelong process, whereby old bone is removed by osteoclasts (bone resorption) and new bone is formed by osteoblasts (bone formation).1,2 Osteocytes, which act as mechanosensors/endocrine cells, and bone lining cells3 are also involved in bone remodelling.4 Myriad pathophysiological factors affecting bone remodelling have been observed in skeletal diseases such as osteoporosis, arthritis and periodontal disease.5 Oxidative stress is one of the pathophysiological factors affecting bone remodelling. Oxidative stress stimulates osteoclast differentiation, thereby enhancing bone resorption.6,7 Reactive oxygen species (ROS) stimulate the apoptosis of osteoblasts and osteocytes, thus affecting bone formation. ROS also activate mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases (ERK1/2), c-Jun-N terminal kinase (JNK) and p38, and enhance osteoclastogenesis and bone resorption.811 These phenomena skew the bone remodelling process in favour of bone loss.

Antioxidants are compounds which reduce free radicals and oxidative stress.12 Antioxidants have been reported to promote differentiation of osteoblasts, bone formation and survival of osteocytes, as well as suppressing osteoclast differentiation and activity.8,1315 Some studies associate the age-related reduction in circulating antioxidants to osteoporosis in rats and women.1618 A decline in antioxidant levels has been reported to promote bone loss by triggering the tumour necrosis factor-alpha (TNF)-dependent signalling pathway,6 while administration of antioxidants, such as vitamin C, E, N-acetylcysteine and lipoic acid, have been reported to exert favourable effects in animal models of osteoporosis1921 and individuals with osteoporosis.2225

Caffeic acid (CA) is a metabolite of hydroxycinnamate and phenylpropanoid commonly synthesized by all plant species. It is a polyphenol present in many food sources like coffee, tea, wine, blueberries, apples, cider, honey and propolis.26 CA and its major derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) are reported to possess potential antibacterial, antidiabetic, antioxidant, anti-inflammatory, antineoplastic and cardioprotective activities (reviewed in2729). As a potent antioxidant, CA has been demonstrated to decrease lipoperoxyl radicals (ROO) by donating a hydrogen atom to its corresponding hydroperoxide, which terminates the lipid peroxidation chain reaction. It also inhibits human low-density lipoprotein (LDL) oxidation induced by cupric ions.30 Furthermore, it interacts with other compounds, such as -tocopherol, chlorogenic and caftaric acids, to exert more potent antioxidant activity in a variety of different systems.3133 Therefore, the antioxidant activities of CA might protect against the negative effects of oxidative stress on bone cells and the skeletal system. This systematic review aims to summarise the effects of CA and its derivatives on bone cells and bone in literature.

A systematic literature search was conducted from July until November 2020 using PubMed, Scopus, Cochrane Library and Web of Science databases to identify studies on the effects of caffeic acid on bone and bone cells including osteoblasts, osteoclasts and osteocytes. The search string used was (1) caffeic acid AND (2) (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes).

Studies with the following characteristics were included: (1) original research article with the primary objective of determining the effects of caffeic acid on bone and bone cells; (2) studies using cellular or animal models, or humans; (3) studies administering caffeic acid as a single compound but not in a mixture or food. Articles were excluded if they (1) do not contain original data; (2) use food rich in caffeic acid or mixtures containing caffeic acid. The bibliography of relevant review articles was traced for potential articles missed during database search. The search results were organised using EndNoteTM software (Clarivate Analytics, Philadelphia, USA). Duplicates were identified using EndNoteTM and confirmed by manual checking.

Two authors (S.O.E. and K.L.P.) searched the same databases using the search string mentioned and screened the search results. All the articles that did not match the selection criteria were excluded. Next, the articles which used caffeic acid in treating models other than bone-related diseases were removed. Finally, articles which used caffeic acid in combination with other compounds were also excluded. Any disagreement on the inclusion or exclusion of articles was resolved through discussion among the two authors. The corresponding author (K.Y.C.) had the final decision on articles included if a consensus could not be reached between authors responsible for screening. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist.34 Steps in the selection process, from identification, screening, eligibility to the inclusion of articles, are shown in Figure 1.

Figure 1 Flowchart of the article selection process.

From the literature search, 381 articles were identified, of which 87 were obtained from PubMed, 182 were from Scopus, 3 from Cochrane Library and 109 from Web of Science. A total of 155 duplicate articles were identified and removed. Of the 226 articles screened, 202 articles were excluded based on the selection criteria, whereby 51 articles did not contain primary data (3 book chapters, 2 commentary and 46 review articles), 147 articles and 2 conference abstracts presented topics irrelevant to the current review, a conference abstract had been published as a full-length research article and another conference abstract did not contain sufficient experiment details (Supplementary Material). Finally, 24 articles fulfilling all criteria mentioned were included in the review.

The included studies were published between 2006 and 2020. Seven studies were in vitro experiments using mouse bone marrow macrophages (BMMs), RAW264.7, RAW D and MG63 osteoblast cell lines3541 while 19 studies were in vivo studies using Sprague Dawley/Sprague Dawley albino rats, Wistar/Wistar albino rats, Balb/c mice, lipopolysaccharide (LPS)-resistant C3H/HEJ mice, C57BL/6J mice and ICR mice.35,38,4258 No human studies on this topic were reported.

Six in vitro studies focused on the effects of CA on osteoclast differentiation from haematopoietic cells using macrophage colony-stimulating factor (M-CSF), receptor activator of NF-B (RANK) ligand (RANKL) or TNF-,3539,41 while one in vitro study focused on the effect of CA on osteoblasts using MG63 osteoblast cell line.40 Four in vitro studies used CA doses between 0.15 M.35,37,38,40 Ang et al.36 used doses between 00.3 M and Sandra et al.41 and Sandra and Ketherin39 used a dose of 10 g/mL (55.5 M). The treatment period was 57 days for the differentiation of osteoclasts.

For animal studies, Duan et al.,55 Zawawi et al.,58 William et al.,51 Wu et al.,38 Zych et al.49 and Folwarczna et al.48,52 used CA or its derivatives at doses between 0.550 mg/kg via oral or intraperitoneal (i.p.) administration. Ucan et al.,57 Erdem et al.,53 Cicek et al.,54 Yigit et al.,45 Yildiz et al.50 and Tolba et al.56 used doses between 1020 mol/kg/day (2.845.69 mg/kg/day) via i.p. administration. Kizilda et al.4244 and Kazanciolu et al.46,47 used the dose of 10 mmol/kg/day (2.843 g/kg/day) for an i.p. administration, Kazanciolu et al.47 employed 50100 mmol/kg/day (14.2228.43 g/kg/day) for a localised administration, while Ha et al.35 used a collagen sponge soaked with CAPE with the final dose of 250 g/mouse. For oral administration, first-pass effect might affect the enteric absorption of CA or its derivatives.59 For i.p. administration, the injection is commonly performed at the lower left or right quadrant of the abdomen. The peritoneum can absorb the compounds fast and reach systemic circulation with greater bioavailability with fewer handling errors.60

The bone-related disease models used included ovariectomy (OVX)- or glucocorticoids (dexamethasone)-induced osteoporosis, polyethylene particle-induced bone defect and osteolysis, electromagnetic force (EMF)-stimulated bone loss, osteotomy- or anti-collagen antibody-induced arthritis (CAIA) and rapid maxillary expansion (RME) and LPS-induced periodontitis. The endpoints studied included bone microstructure, histomorphometry, bone remodelling and oxidative status. The effects of CA and its derivatives on bone remodelling have been summarized in Table 1.

Melguizo-Rodrguez et al. reported that 24-hour CA (1 M) incubation increased the number of MG63 osteoblast cells compared with control.40 Gene expression studies revealed that CA increased the expression of osteoblast-related genes such as bone morphogenetic protein-2 and -7 (BMP-2 and BMP-7), transforming growth factor-beta 1 (TGF-1), transforming growth factor-beta receptor 1, 2 and 3 (TGF-R1, TGF-R2 and TGF-R3) and osteoblastogenesis genes including Runt-related transcription (RUNX-2), alkaline phosphatase (ALP), collagen type 1 (COL-I), osterix (OSX) and osteocalcin (OSC).40 Additionally, pretreatment of CA (10 g/mL or 55.5 M) on RAW D cells for 2 h also significantly inhibited the RANKL and TNF-induced osteoclastogenesis with the suppression of p38 MAPK phosphorylation and tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells (OCLs) formation.39 Similarly, pretreatment of CA (0.1, 1 and 10 g/mL or 0.555, 5.55 and 55.5 M) on RAW D cells and BMMs for 3 days significantly inhibited the RANKL and TNF-induced osteoclastogenesis and NF-B activity in RAW-D cells and RANKL, TNF and M-CSF-induced osteoclastogenesis in BMMs.41

On the other hand, CAPE treatment (00.3 M; 57 days) suppressed the formation of TRAP-positive OCLs on RANKL-treated RAW264.7 cells and BMMs.36 Apoptosis occurred in CAPE-treated RAW264.7 cells with the disruption of the microtubule network in OCLs.36 Similarly, Kwon et al. reported that CAPE treatment (0.15 M) for 5 days suppressed OCLs formation from RANKL-stimulated RAW264.7 cells.37 Another study by Ha et al. treating M-CSF and RANKL-stimulated BMMs with CAPE (05 M for 57 days) also showed decreased OCLs formation in a concentration-dependent manner.35 The amount of TRAP-positive OCLs was decreased upon 0.1 and 0.5 M CAPE treatment by 30% and 95% respectively.35 No OCL formation was observed upon 1 M CAPE treatment.35 The anti-osteoclastogenic activities of CAPE are mainly contributed by its anti-inflammatory and antioxidant properties. Mechanistically, CAPE reduces superoxide anion generation by downregulating the nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1) expression through the interruption of nuclear factor-kappa B (NF-B) and c-Jun N-terminal kinase (JNK) signalling pathways.37 CAPE suppresses RANKL-mediated activation of the NF-B pathway by downregulating NF-B p65 subunit expression and its nuclear translocation,37 suppressing nuclear factor of activated T cells (NFAT) activities36 and degradation of NF-B inhibitor (IB),36,37 as well as inducing the degradation of IB kinase (IKK).37 CAPE also suppresses the expression and activation of JNK and its downstream transcription factors, such as c-Fos and c-Jun, which subsequently interrupt the protein activator-1 (AP-1) complex formation.37 Additionally, CAPE suppressed RANKL-induced activation of the Nox1 by inhibiting the Nox p47PHOX subunit translocation to the cell membrane and downregulation of Ras-related C3 botulinum toxin substrate 1 (Rac1) expression.37

On the other hand, Wu et al. reported that CADPE (0.15 M for 7 days) also concentration-dependently reduced OCL formation in the M-CSF and RANKL-stimulated BMMs and RAW264.7 cells.38 Mechanistic and characterisation examination revealed that CADPE suppressed RANKL-induced tumour necrosis factor receptor-associated factor 6 (TRAF6) activation and protein kinase B (PKB or also known as Akt) and activation of major MAPKs including ERK, JNK and p38.38 Subsequently, CADPE suppressed downstream expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), nuclear translocation of c-Fos protein and expression of osteoclastic markers, such as TRAP and cathepsin K, possibly through the non-receptor tyrosine kinase c-Src signalling.38 Interestingly, CADPE did not significantly affect the NF-kB signalling pathway and M-CSF-induced proliferation and differentiation of BMMs.

Supplementation of CA in animal models of bone loss yielded heterogeneous findings.48,49,52 This observation might be attributable to oral administration. Folwarczna et al. reported that CA (5 and 50 mg/kg, by stomach tube for 4 weeks) improved the bone mechanical properties by increasing the width of the trabecular metaphysis of the femur and decreasing the transverse growth in endosteal of the femur in OVX rats.48 Folwarczna et al. then demonstrated that CA (10 mg/kg/day; oral administration for 4 weeks) could reduce the width of tibial periosteal and endosteal osteoid compared with untreated OVX rats.52 However, CA did not promote or reduce the resorption of compact bone in the tibia of OVX-induced osteoporotic rats as evidenced by negligible changes of bone mass, bone mineral mass, bone mass/body mass ratio and bone mineral mass/body mass ratio.52 On the other hand, Zych et al. reported that CA at a similar dose (10 mg/kg/day; by stomach tube for 4 weeks) worsened the bone mechanical properties of healthy female Wistar Cmd:(WI)WU rats by decreasing the load of fracture at the femoral neck, decreasing the width of periosteal osteoid in the tibia and decreasing the width of the epiphysis and metaphysis trabecular in the femur compared with the negative control group.49

CAPE is the most extensively studied caffeic acid derivative in animal studies. The beneficial effects on new bone formation and healing upon systemic administration of CAPE had been reported.46,47,53,57 Erdem et al. reported that a low dose of CAPE (10 mol/kg; i.p. injection for 22 days) increased new bone formation and bone strength by increasing maximum torsional fracture momentum and degree of rigidity compared with negative control in rats that underwent unilateral femoral lengthening (osteotomy).53 Similarly, a 30-day i.p. injection of CAPE (10 mol/kg/day) also increased bone healing level in Sprague Dawley rats with cranial critical size bone defect.57 A higher dose of CAPE (10 mmol/kg/day, i.p. for 20 days) also further promoted the RME procedure-induced new bone formation in midpalatal suture of male Sprague Dawley rats.47 Similarly, a longer treatment period of CAPE (10 mmol/kg/day; i.p. injection for 28 days) also significantly promoted bone healing by increasing the total new bone areas in surgical-induced calvarial defects of male Wistar rats compared with the negative control.46 However, localised administration of CAPE (28 days) on surgical-induced calvarial defects by pre-mixing 50 and 100 mmol/kg CAPE solutions with gelatin sponges did not significantly improve the new bone formation.46

Localised and systemic administration of CAPE was reported to be beneficial in reducing osteolysis and bone loss.35,4245,50,5456,58 Ha et al. reported that collagen sponge implant impregnated with 250 g CAPE and RANKL could reduce osteoclastogenesis with significantly lesser TRAP-stained area in mouse calvariae compared with implants with RANKL only.35 Subcutaneous injection of CAPE (1 mg/kg/day for 10 days) reduced the polyethylene particle-induced calvarial osteolysis, surface bone resorption and TRAP-positive cells formation with an increase of bone volume (BV) on LPS-resistant C3H/HEJ female mice.58 However, no significant changes were observed in carboxy-terminal cross-linked type 1 collagen (CTX-1) and osteoclast-associated receptor levels among untreated and CAPE-treated rats with calvarial osteolysis.58

Similarly, Duan et al. reported that lower dose and frequency of CAPE injection (0.5 mg/kg twice a week; i.p. injection for 4 weeks) also increased the BV and trabecular number (Tb.N) due to the decrease of bone osteoclast formation (evidenced by decreased osteoclast number/bone perimeter) in OVX mice.55 Tolba et al. also reported that i.p. injection of CAPE (10 and 20 mol/kg) for 3 weeks increased femur weight and length in rats with dexamethasone-induced bone loss.56 The preservation of skeletal health in their study was associated with an improved antioxidant defence, such as higher levels of glutathione (GSH) and superoxide dismutase (SOD), and the reduction of malondialdehyde (MDA, lipid peroxidation product).56 This event led to an increase of osteoblastogenesis indicated by upregulation of RUNX-2 and ALP (osteoblast marker) levels56 On the other hand, decreased RANKL/osteoprotegerin (OPG) ratio was observed with CAPE treatment, indicating the suppression of osteoclastogenesis, which was further confirmed by lower acid phosphatase level and TRAP activity.56 In another study by Yildiz et al., CAPE (10 mol/kg/day; i.p. injection for 22 days) also increased the spine and femur BMD in rats with EMF-induced bone loss.50 Similarly, Cicek et al. reported a longer treatment of CAPE (10 mol/kg/day; i.p. injection for 28 days) also significantly improved the mechanical strength of cortical bone by increasing the breaking force, bending strength and total fracture energy in rats with EMF-induced bone loss compared with negative control.54

Additionally, a study by Wu et al. treated mice with an OVX-induced bone loss with a moderately high dose of CADPE (10 mg/kg; i.p. injection) every 2 days for 3 months.38 Results showed that CADPE could increase the BV fraction (BV/TV) and Tb.N, as well as decreased trabecular spacing (Tb.Sp) compared with the negative control.38 The improvement in the bone structure was contributed by reduced osteoclast number and eroded surface on the bone.38 Assessment of bone remodelling markers also revealed that serum TRAP5b and CTX-1 levels were reduced in CADPE-treated group compared with the negative control.38

On the other hand, CAPE was effective in reducing periodontitis-related bone loss and osteolysis.4245 CAPE (10 mol/kg/day, i.p. for 14 days) significantly reduced the subgingival ligature placement-induced periodontitis-mediated articular bone loss, histopathological features and severity of periodontal inflammation with lesser polymorphonuclear cells (PMNLs) infiltration in the junctional epithelium and connective tissues among Wistar albino rats.45 CAPE also suppressed the periodontitis-upregulated interleukin (IL)-1, IL-6, IL-10, TNF, MDA levels and the percentage of gingival apoptosis with the parallel restoration of periodontitis-downregulated GSH and glutathione peroxidase (GPx).45 Administration of high-dose CAPE (10 mmol/kg/day; i.p. for 15 days) in streptozotocin (STZ)-induced diabetic male Sprague Dawley rats reduced RANKL-positive osteoclast number, IL-1 levels, oxidative stress index (OSI), alveolar bone loss and histological analysis score in LPS-induced periodontitis. The treated rats also suffered lesser inflammatory reactions, ulcers and hyperemia.42 Similar changes of osteoclast number, IL-1 and OSI were observed in male Sprague Dawley rats with chronic stress and LPS-induced periodontitis treated with CAPE (10 mmol/kg/day, i.p. for 14 days).44 In addition, CAPE also increased the mesial and distal periodontal bone supports (MPBS and DPBS) in these rats.44 The effects of CAPE were sustained with a longer treatment period of CAPE (10 mmol/kg/day, i.p. for 28 days) on male Sprague Dawley rats with LPS-induced periodontitis.43

In contrast to the above findings, Williams et al. reported that subcutaneous injection of CAPE (1 mg/kg; at day 3, 7 and 10) did not reduce paw inflammation or bone loss in CAIA mice.51 Cartilage and bone degradation, as well as TRAP-positive cells on the bone surface and soft tissues, were still apparent in the supplemented CAIA group compared with the normal control.51

This systematic review found that although CA and its derivatives is a potential anti-osteoporosis agent by suppressing the formation of osteoclasts and their bone resorption activity, it worsened bone mechanical properties in some cases. The anti-osteoclastogenesis action of CA and its derivatives was mediated by the antioxidant activities, which blocked RANKL-induced TRAF6/Akt and MAPK signalling, as well as M-CSF/c-Src signalling. In animals, CA and its derivatives (mainly CAPE) prevented bone resorption in rodent calvariae when implanted in situ, facilitated the healing of bone defects, preserved bone structure and improved mechanical strength in osteoporosis models induced by OVX, dexamethasone, osteotomy, LPS-mediated periodontitis and EMF. However, CA did not alter bone resorption in OVX-induced osteoporotic rats and worsened the mechanical properties in normal rats. Additionally, CAPE did not suppress bone loss in rats with CAIA-induced bone loss.

Osteoblasts are bone-forming cells derived from bone marrow mesenchymal stem cells and are responsible for the synthesis, secretion and mineralisation of bone matrix.61 The expression of osteoblast markers was increased following CA or CAPE supplementation, an indication that CA and CAPE stimulated osteoblast proliferation, differentiation and maturation.40,56 Osteoblasts and osteocytes regulate the formation of osteoclasts through RANKL/OPG axis. Osteoblasts and osteocytes synthesise RANKL, which binds to RANK to activate the canonical pathway for osteoclastogenesis. They also secrete OPG, which is a decoy receptor for RANKL to suppress osteoclastogenesis. The production of RANKL is stimulated under conditions such as oestrogen deficiency62 and oxidative stress.63 Osteoclastogenesis can also be stimulated via a non-canonical pathway, for instance, through the binding of TNF with TNF receptor I or II.64 Glucocorticoids are potential modulators of RANKL/OPG axis, whereby dexamethasone is shown to downregulate OPG levels in osteoblasts.65 Tolba et al. showed that the RANKL/OPG level reduced in rats induced with dexamethasone with CAPE treatment.56 Other cellular studies showed that CA and its derivatives suppressed RANKL- and TNF-induced formation of OCLs from haematopoietic cells,3539 indicating that CA and its derivatives suppressed both canonical and non-canonical osteoclastogenesis.

The complex formed by the binding of RANKL to RANK causes the recruitment of the adaptor molecules tumour necrosis factor receptor-associated factors (TRAFs), including TRAF6.66 This event leads to the activation of several downstream signalling pathways, including c-Src/Akt/phosphatidylinositol 3-kinase and MAPKs (ERK/p38/JNK). CADPE was shown to suppress RANKL-induced activation of TRAF6 activation and the subsequent signalling pathways in multiple osteoclast progenitors, such as BMMs,38 RAW264.738 and RAW D cells.39 Sandra and Ketherin suggested that the downregulation of p38 is the key step of CA-mediated osteoclastogenesis.39 Upon activation, p38 initiates osteoclastogenesis by inducing NF-B and NFATc1 expression.67,68 Inhibition of p38 MAPK reduces RANKL (canonical) and TNF-induced (non-canonical) osteoclast formation.69

The NF-B pathway is another signalling pathway downstream of TRAFs critical for osteoclast differentiation and bone reabsorption activity. Upon activation, IKK (consisting of IKK, IKK and IKK) phosphorylates and degrades IB, which enables translocation of NF-B p65/p50 heterodimers into the nucleus to allow transcription of osteoclast-related genes.70 Kwon et al. demonstrated that the anti-osteoclastogenesis effects of CAPE were mediated via the degradation of total IKK, thereby preventing the phosphorylation and degradation of IB and subsequently suppresses the nuclear translation of p65.37 On the other hand, Wu et al. reported that CADPE did not affect phosphorylation or degradation of IB, as well as nuclear translocation, and DNA-binding activity of p65.38 This observation suggests that compared with CAPE, CADPE does not influence the NF-B signalling pathway.

ROS are one of the important secondary signals in the early stages of osteoclast differentiation.71,72 These ROS are mainly produced as superoxide anions by Nox1.73 Blocking of Nox1 ameliorates ROS production and the downstream MAPKs (JNK, p38 and ERK) and NF-B activation74 and subsequently suppresses the osteoclast formation.71 The reduction of Nox 1 and Rac1 expression by CAPE is accompanied by RANKL-downstream signalling, denoting that anti-osteoclastogenesis effects of CAPE are dependent on suppression of Nox1-mediated superoxide anion production. Besides, dexamethasone has been reported to increase the expression of oxidative stress-related genes in human osteoblasts.75 Tolba et al. showed that CAPE increased GSH and SOD but reduced MDA in the bone of the rats exposed to dexamethasone, indicating an improvement of redox status in the skeletal environment.56 Additionally, CAPE also reduced the OSI and bone loss with an improvement of bone support in rats with LPS-induced periodontitis.

NFATc1 is the master regulator of osteoclast-related gene expression, and it is activated by c-Fos and NF-B.76 Ha et al. observed that CAPE inhibited the recruitment of NF-B to NFATc1 promoter, and the combined effect of NF-B inhibition on c-Fos and NFATc1 may have caused CAPE to suppress osteoclastogenesis effectively.35 Holland et al. demonstrated a new fluorinated derivative of CAPE possesses potent anti-osteoclastogenic properties on RAW 264.7 cells by downregulating NFATc1 via suppression of c-Fos and NF-B signalling pathways.77 Besides, this new fluorinated CAPE also exhibits improved stability with a 2-fold higher potency than CAPE.77 On the other hand, although CADPE did not alter NF-B signalling, it still could suppress NFATc1 and other osteoclast-related markers, indicating other mechanisms of suppression could be involved, for instance, c-Src and MAPKs signalling pathways.38

Matrix metalloproteinases (MMPs), including gelatinases (MMP-2 and MMP-9) are examples of zinc-dependent extracellular matrix-degrading enzymes, which actively participate in bone resorption.78 MMPs are expressed as inactive proenzymes or zymogens that can be activated by several mediators including AP-1, NF-B, TNF and TGF.78 Currently, there is no study conducted to investigate the inhibitory effects of CA and CAPE on osteoclastic MMPs activity and its subsequent linkage in bone resorption; interestingly, CA and CAPE were reported to inhibit MMP-9 activity in human hepatocellular carcinoma HEP3B cells.79,80 This observation renders an interesting research gap in osteoclastic MMP inhibition upon CA and its derivatives treatment.

Suppression of osteoclastogenesis by CA or its derivatives have significant therapeutic potential against bone disorders induced by excessive bone resorption. Bone loss after osteotomy is a rapid process that affects both fractured and unfractured bone and may be incompletely reversible.81 CAPE was reported to improve bone formation and mechanical strength of bone in osteotomy.53 Exposure to EMF radiation caused by high-voltage transmission lines and transformers could affect bone health through decreased BMD, serum calcium and ALP level leading to the increase of bone resorption.82 CAPE increased the spine and femur BMD levels50 and increased mechanical strength of bones54 in rats exposed to EMF radiation. Total hip arthroplasty without cement often caused osteolysis induced by polyethylene particles.83 CAPE was shown by Zawawi et al. to prevent calvarial bone resorption in a murine polyethylene particle-induced osteolysis model.58 Therefore, biomaterials impregnated with CA or its derivatives could be adopted to prevent osteolysis in the arthroplasty procedure. CA has been incorporated in chitosan/(3-chloropropyl) trimethoxysilane scaffold for hard-tissue engineering applications and this adopted material exhibits antibacterial and anticancer effects.84 Ucan et al. observed that CAPE increased cranial bone healing in rats with critical size bone defect, suggesting that it could be administered systematically or locally to treat bone fracture/defect healing.57

Similarly, CAPE also effectively reduced the articular bone loss, inflammatory cytokines production and oxidative stress in rats with LPS-mediated periodontitis. Additionally, Wu et al.38 and Duan et al.55 demonstrated that CADPE prevented the ovariectomy-induced bone loss by suppressing osteoclast activity in a mouse model, while Folwarczna et al. showed increased width of trabecular metaphysis in the femur of OVX rats.48 Similarly, Tolba et al. showed improved bone formation and skeletal health in rats with dexamethasone-induced bone loss upon receiving CAPE.56 Additionally, CA and its derivatives may be involved in oestrogen production and signalling. Zych et al. reported that an oral administration of CA (10 mg/kg/day for 4 weeks) significantly restored the serum oestradiol levels in OVX rats.85 Interestingly, CA at 10 and 100 M did not cause any alteration in calcium content in the femoral-diaphyseal and metaphyseal ex vivo culture, suggesting its bone-protecting effect may not involve calcium metabolism and regulation.86 Additionally, CAPE was reported as a selective human oestrogen receptor agonist with the EC50 value of 3.72 M in oestrogen-responsive element transcription.87 A recent in silico study by Zhao et al. suggested potential osteoimmunological effects of CAPE, which may explain its biological activities on both immune and skeletal systems.88 However, the findings from this modelling study requires further validation through in vitro and in vivo models. As oestrogen deficiency due to menopause and glucocorticoids present the most significant cause of primary and secondary osteoporosis globally, CA and its derivatives have the potential to be used as an adjuvant therapy to existing osteoporosis management strategies. The mechanisms of action of CA and its derivatives in osteoclastogenesis have been summarized in Figure 2.

Figure 2 Mechanism of action of caffeic acid and its derivatives.

Abbreviations: , decrease or downregulate; ?, unknown mechanism; Akt, protein kinase B; AP-1, activator protein 1; CA, caffeic acid; CADPE; caffeic acid 3,4-dihydroxy-phenethyl ester; CAPE, caffeic acid phenethyl ester; c-Src, cellular sarcoma tyrosine kinase; ERK1/2, extracellular signal-regulated kinases 1/2; GM-CSF, granulocyte-macrophage colony-stimulating factor; Grb2, growth factor receptor-bound protein 2; IFN-, interferon-gamma; IL, interleukin; IL1R, interleukin-1 receptor; IB, NF-B inhibitor protein; IKK, IB kinase; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; M-CSF-R, M-CSF receptor; MAPKs, mitogen-activated protein kinases; NFAT, nuclear factor of activated T cells; NF-B, nuclear factor kappa B; NIK, MAPK kinase kinase 14; Nox1, nicotinamide adenine dinucleotide phosphate oxidase 1; OPG, osteoprotegerin; PI3k, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; ROS, reactive oxygen species; TAK, MAPK kinase kinase 7; TLR4, Toll-like receptor 4; TNF, tumour necrosis factor-alpha; TNFR1/2, TNF receptor 1/2; TRAF2, tumour necrosis factor receptor-associated factor 2; TRAF6; tumour necrosis factor receptor-associated factor 6.

Regardless of the positive effects of CA on bone status, some studies have reported negative effects associated with supplementation of CA and its derivatives. CA supplementation did not affect the bone resorption52 and reduced transverse growth of endosteal in femur48 of rats with OVX-induced osteoporosis. In normal rats, CA supplementation even negatively affected their bone mechanical properties.49 Moreover, CAPE supplementation has been reported to stimulate the synthesis of PGE2,89 which mediates osteoclastogenesis through RANKL stimulation and activation of the NF-B pathway.90 This event will eventually increase TRAP-positive OCLs. Similarly, Williams et al. showed that CAPE did not suppress osteoclastogenesis in rats with CAIA.51

In term of safety, the International Agency for Cancer Research classifies CA as Class 2B (possibly carcinogenic to humans),91 and it was reported to induce renal tubular cell hyperplasia, forestomach hyperplasia, renal cell adenoma and forestomach cancer in rodents.9294 CA has been reported to be non-mutagenic and non-clastogenic.91 Therefore, its carcinogenicity may involve epigenetic modification. Human toxicity and carcinogenicity of CA and its derivatives remain unknown. CA also showed anti-implantation activity in pregnant mice at a median effective dose of 4.26 mg/kg/day.95 Similarly, 5 mg/kg/day and 150 mg/kg of CA in mice demonstrated anti-implantation activity in early pregnancy.96 On the other hand, 0.15 mg/kg/day, 5 mg/kg/day and 150 mg/kg/day of CA for 21 days in mice showed no maternal toxicity, foetal teratogenesis or post-natal effects on pup development and mortality.96 The same experiment stated that the no-observed-adverse-effect level of CA for pregnant female mice was 0.15 mg/kg/day.96 Therefore, high-dose CA should be cautioned in humans, especially pregnant women.

Several common limitations can be identified from the studies reviewed. Most studies did not adopt a positive control to compare against the anti-osteoclastogenesis or anti-osteoporosis effect of CA. Therefore, the therapeutic effects of CA and currently available anti-resorptive therapy cannot be compared. Although osteoblastogenesis and bone formation are also important in bone remodelling, evidence of CA on these processes is limited in the literature. The actions of CA in humans cannot be confirmed due to the lack of human clinical trials. These aspects can be improved in future studies.

The current review also has several limitations. We only considered articles indexed by PubMed, Scopus, Cochrane Library and Web of Science; therefore, non-indexed articles could be overlooked. We only selected articles studying CA or its derivatives as a single compound to understand its mechanism of action properly without other interference, but not a mixture of compounds or natural products rich in CA. CA are present in foods, and interaction with other compounds in the food matrix might alter its absorption, bioavailability and action on the target tissue. Moreover, the heterogeneous findings of CA in bone loss reduction upon oral administration further emphasise these possibilities.

The current preclinical evidence agrees that CA and its derivatives exert promising skeletal protective effects by inhibiting osteoclastogenesis and bone resorption, but literature on bone formation is limited. Notwithstanding that, the skeletal effects of CA and its derivatives in models of normal bone health should be investigated because the limited studies available show undesirable effects. Human clinical trials to validate the skeletal effects of CA are lacking. Therefore, a well-planned clinical trial should be conducted to confirm the potential of CA as an antiresorptive agent. This information is critical for CA and its derivatives to be incorporated as part of the strategies to prevent bone loss.

The researchers are funded by Universiti Kebangsaan Malaysia through Research University Grant (GUP-2020-021). S.O.E. and K.L.P. are post-doctoral researchers funded by Universiti Kebangsaan Malaysia through FPR-1 and RGA-1 grants.

The authors report no conflicts of interest in this work.

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5. Jiao H, Xiao E, Graves DT. Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep. 2015;13(5):327335. doi:10.1007/s11914-015-0286-8

6. Lean JM, Jagger CJ, Kirstein B, et al. Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation. Endocrinology. 2005;146(2):728735. doi:10.1210/en.2004-1021

7. Huh YJ, Kim JM, Kim H, et al. Regulation of osteoclast differentiation by the redox-dependent modulation of nuclear import of transcription factors. Cell Death Differ. 2006;13(7):11381146. doi:10.1038/sj.cdd.4401793

8. Fontani F, Marcucci G, Iantomasi T, et al. Glutathione, N-acetylcysteine and lipoic acid down-regulate starvation-induced apoptosis, RANKL/OPG ratio and sclerostin in osteocytes: involvement of JNK and ERK1/2 signalling. Calcif Tissue Int. 2015;96(4):335346. doi:10.1007/s00223-015-9961-0

9. Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229238. doi:10.1002/jbmr.320

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12. Soares DG, Andreazza AC, Salvador M. Avaliao de compostos com atividade antioxidante em clulas da levedura saccharomyces cerevisiae. Rev Bras Cienc Farm. 2005;41:95100. doi:10.1590/S1516-93322005000100011

13. Romagnoli C, Marcucci G, Favilli F, et al. Role of GSH/GSSG redox couple in osteogenic activity and osteoclastogenic markers of human osteoblast-like Saos-2 cells. FEBS J. 2013;280(3):867879.

14. Banfi G, Iorio EL, Corsi MM. Oxidative stress, free radicals and bone remodeling. Clin Chem Lab Med. 2008;46(11):15501555. doi:10.1515/CCLM.2008.302

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18. Maggio D, Barabani M, Pierandrei M, et al. Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab. 2003;88(4):15231527. doi:10.1210/jc.2002-021496

19. Lean JM, Davies JT, Fuller K, et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest. 2003;112(6):915923. doi:10.1172/JCI200318859

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21. Mohamad S, Shuid AN, Mohamed N, et al. The effects of alpha-tocopherol supplementation on fracture healing in a postmenopausal osteoporotic rat model. Clinics (Sao Paulo). 2012;67:10771085. doi:10.6061/clinics/2012(09)16

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24. Morton DJ, Barrett-Connor EL, Schneider DL. Vitamin c supplement use and bone mineral density in postmenopausal women. J Bone Miner Res. 2001;16(1):135140. doi:10.1359/jbmr.2001.16.1.135

25. Mainini G, Rotondi M, Di Nola K, et al. Oral supplementation with antioxidant agents containing alpha lipoic acid: effects on postmenopausal bone mass. Clin Exp Obstet Gynecol. 2012;39(4):489493.

26. Clifford MN. Chlorogenic acids and other cinnamates nature, occurrence, dietary burden, absorption and metabolism. J Sci Food Agric. 2000;80(7):10331043. doi:10.1002/(SICI)1097-0010(20000515)80:7<1033::AID-JSFA595>3.0.CO;2-T

27. Espindola KMM, Ferreira RG, Narvaez LEM, et al. Chemical and pharmacological aspects of caffeic acid and its activity in hepatocarcinoma. Front Oncol. 2019;9:541. doi:10.3389/fonc.2019.00541

28. Magnani C, Isaac VLB, Correa MA, et al. Caffeic acid: a review of its potential use in medications and cosmetics. Anal Methods. 2014;6(10):32033210. doi:10.1039/C3AY41807C

29. Armutcu F, Akyol S, Ustunsoy S, et al. Therapeutic potential of caffeic acid phenethyl ester and its anti-inflammatory and immunomodulatory effects (review). Exp Ther Med. 2015;9(5):15821588. doi:10.3892/etm.2015.2346

30. Nardini M, DAquino M, Tomassi G, et al. Inhibition of human low-density lipoprotein oxidation by caffeic acid and other hydroxycinnamic acid derivatives. Free Radic Biol Med. 1995;19(5):541552. doi:10.1016/0891-5849(95)00052-Y

31. Laranjinha J, Vierira O, Almeida L, et al. Inhibition of metmyoglobin/H2O2-dependent low density lipoprotein lipid peroxidation by naturally occurring phenolic acids. Biochem Pharmacol. 1996;51(4):395402. doi:10.1016/0006-2952(95)02171-X

32. Meyer AS, Donovan JL, Pearson DA, et al. Fruit hydroxycinnamic acids inhibit human low-density lipoprotein oxidation in vitro. J Agric Food Chem. 1998;46(5):17831787.

33. Fukumoto LR, Mazza G. Assessing antioxidant and prooxidant activities of phenolic compounds. J Agric Food Chem. 2000;48(8):35973604. doi:10.1021/jf000220w

34. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the prisma statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097

35. Ha J, Choi H-S, Lee Y, et al. Caffeic acid phenethyl ester inhibits osteoclastogenesis by suppressing NF kappaB and downregulating NFATc1 and c-Fos. Int Immunopharmacol. 2009;9(6):774780. doi:10.1016/j.intimp.2009.03.001

36. Ang ES, Pavlos NJ, Chai LY, et al. Caffeic acid phenethyl ester, an active component of honeybee propolis attenuates osteoclastogenesis and bone resorption via the suppression of RANKL-induced NF-kappaB and NFAT activity. J Cell Physiol. 2009;221(3):642649. doi:10.1002/jcp.21898

37. Kwon YB, Wang FF, Jang HD. Anti-osteoclastic effect of caffeic acid phenethyl ester in murine macrophages depends upon the suppression of superoxide anion production through the prevention of an active-nox1 complex formation. J Nutr Biochem. 2018;58:158168. doi:10.1016/j.jnutbio.2018.03.023

38. Wu X, Li Z, Yang Z, et al. Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-B ligandinduced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+nuclear factor of activated T-cells cytoplasmic 1 signaling pathways. J Bone Miner Res. 2012;27(6):12981308. doi:10.1002/jbmr.1576

39. Sandra F, Ketherin K. Caffeic acid inhibits RANKL and TNF--induced phosphorylation of p38 mitogen-activated protein kinase in RAW-D cells. Indones Biomed J. 2018;10(2):140143. doi:10.18585/inabj.v10i2.437

40. Melguizo-Rodrguez L, Manzano-Moreno FJ, Illescas-Montes R, et al. Bone protective effect of extra-virgin olive oil phenolic compounds by modulating osteoblast gene expression. Nutrients. 2019;11(8):1722. doi:10.3390/nu11081722

41. Sandra F, Kukita T, Tang QY, et al. Cafeic acid inhibits NFB activation of osteoclastogenesis signaling pathway. Indones Biomed J. 2011;3(3):216222. doi:10.18585/inabj.v3i3.153

42. Kzlda A, Arabac T, Albayrak M, et al. A biochemical and immunohistochemical study of the effects of caffeic acid phenethyl ester on alveolar bone loss and oxidative stress in diabetic rats with experimental periodontitis. Biotech Histochem. 2020;95(6):456463. doi:10.1080/10520295.2020.1718756

43. Kzlda A, Arabac T, Albayrak M, et al. Therapeutic effects of caffeic acid phenethyl ester on alveolar bone loss in rats with endotoxin-induced periodontitis. J Dent Sci. 2019;14(4):339345. doi:10.1016/j.jds.2019.03.011

44. Kzlda A, Arabac T, Albayrak M, et al. Evaluation of caffeic acid phenethyl ester administration in chronically stressed rats with experimental periodontitis. Cumhur Dent J. 2019;22(1):114120.

45. Yiit U, Krzolu FY, Uuz AC, et al. Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis? Arch Oral Biol. 2017;81:6168. doi:10.1016/j.archoralbio.2017.04.017

46. Kazancioglu HO, Bereket MC, Ezirganli S, et al. Effects of caffeic acid phenethyl ester on wound healing in calvarial defects. Acta Odontol Scand. 2015;73(1):2127. doi:10.3109/00016357.2014.942876

47. Kazancioglu HO, Aksakalli S, Ezirganli S, et al. Effect of caffeic acid phenethyl ester on bone formation in the expanded inter-premaxillary suture. Drug Des Devel Ther. 2015;9:64836488. doi:10.2147/DDDT.S97797

48. Folwarczna J, Pytlik M, Zych M, et al. Effects of caffeic and chlorogenic acids on the rat skeletal system. Eur Rev Med Pharmacol Sci. 2015;19(4):682693.

49. Zych M, Folwarczna J, Pytlik M, et al. Administration of caffeic acid worsened bone mechanical properties in female rats. Planta Med. 2010;76(5):407411. doi:10.1055/s-0029-1240603

50. Yildiz M, Cicek E, Cerci SS, et al. Influence of electromagnetic fields and protective effect of cape on bone mineral density in rats. Arch Med Res. 2006;37(7):818821. doi:10.1016/j.arcmed.2006.03.006

51. Williams B, Tsangari E, Stansborough R, et al. Mixed effects of caffeic acid phenethyl ester (CAPE) on joint inflammation, bone loss and gastrointestinal inflammation in a murine model of collagen antibody-induced arthritis. Inflammopharmacology. 2017;25(1):5568. doi:10.1007/s10787-016-0306-z

52. Folwarczna J, Zych M, Burczyk J, et al. Effects of natural phenolic acids on the skeletal system of ovariectomized rats. Planta Med. 2009;75(15):15671572. doi:10.1055/s-0029-1185904

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[Full text] Effects of Caffeic Acid and Its Derivatives on Bone: A Systematic Revi | DDDT - Dove Medical Press

Bone Marrow Stem Cells Comments Off on [Full text] Effects of Caffeic Acid and Its Derivatives on Bone: A Systematic Revi | DDDT – Dove Medical Press | January 22nd, 2021

Introduction

Recent literature reviews suggest that bisphosphonates (BPs) may contribute to the growing number of cases of osteonecrosis involving the maxilla and mandible that are associated with the pathogenesis of BP-related osteonecrosis of the jaw (BRONJ).1 In the discussion concerning BRONJ, a distinction must be made between diseases featuring reduced osseous mineral content, which may be counteracted by BPs (such as those occurring during menopause or in cases of osteoporosis), and cases that present with indications for BPs (such as tumors). BPs have been used in the treatment of multiple myeloma, breast cancer, prostate cancer, and other tumors. In patients with metastatic breast cancer, the bones are affected in around two-thirds of cases. To protect patients from bone fractures and to reduce pain, patients are often prescribed BPs or a special antibody that prevents the breakdown of, and subsequently stabilizes, affected bone. BRONJ is a newly emerging problem that is recognized as a serious complication of BP therapy, primarily following intravenous (IV) administration.2

The concern is that BPs affect the natural remodeling of bone tissues and delay the breakdown of older bone structures. BPs are potent inhibitors of bone resorption and have a chronic effect over a half-life of at least 5 years, possibly exerting their effects for more than 10 years. BRONJ is a seemingly growing epidemic associated with osteonecrosis of the jawbone (ONJ).35 The long-term effects of oncological-related BP treatment on alveolar bone quality include the impact on BP-induced overexpression of alveolar bone remodeling. There are increased osteosclerotic properties in the alveolar bone that are associated with significantly greater bone volume and higher bone density.6,7 The risk of BP therapy is divided into two categories: local and systemic risk factors; thus, a distinction must be made between oral and IV administration. Local oral risk factors for BRONJ in cancer patients include dentoalveolar surgery, dental extraction, and dental implant insertion.8 Periodontal infections also significantly increase the risk of BRONJ in cancer patients.9 In addition, there is a significant correlation between the use of removable prostheses, the administration of high-dose IV BPs, and an increased risk of BRONJ.10 In patients receiving oral BP therapy for the treatment of osteoporosis, the prevalence of BRONJ only increased 0.21% from close to 0%. Systemically, however, there is a much higher risk associated with the IV injection of BPs. This is closely related to the frequent use of BPs in cancer patients who receive a significantly higher total dose over a longer duration.11 The mean and minimum time for the development of ONJ is 1.8 years and 10 months, respectively.12 The risk of BRONJ in cancer patients exposed to BP therapy is from 50100 times higher than in cancer patients treated with a placebo. The BRONJ risk for the RANKL inhibitor denosumab was between 0.7% and 1.9%.13,14 The risk of ONJ in cancer patients treated with high doses of IV BPs appears to be significantly higher: in the range of 110 per 100 patients (depending on therapy duration).15 A recent review reported a wide-ranging BRONJ incidence of 027.5% that was associated with the IV administration of BPs, with an average incidence of 7%.16 The cumulative frequency varied from 0.812.0% and was estimated to be up to 30.0% in some reports.17,18 Despite numerous publications on the subject, the overall pathogenesis of BRONJ does not yet appear to be fully understood. In particular, the reasons why only a subset of patients (<30%) receiving IV BPs develop BRONJ remain unclear. Although most patients that develop BRONJ have a history of tooth extraction or injury, these factors do not fully explain the occurrence of BRONJ.8 The development of BRONJ in edentulous areas in patients with no apparent history of injury suggests that pre-existing conditions, such as subclinical infections or potentially necrotic areas of the jawbone, may contribute to the conditions that lead to the development of BRONJ.

Why does BRONJ develop in up to 30% of individuals following IV BP therapy and not the remaining 70%? This review raises the question of whether little-known or difficult-to-identify, pre-existing, impaired bone remodeling, such as that occurring in aseptic-ischemic osteonecrosis of the jaw (AIOJ), bone marrow defects (BMD), or fatty-degenerative osteonecrosis of the jawbone (FDOJ), represents a local risk factor in the development of BRONJ.

There is still a limited scientific understanding of the relationship between ONJ and BPs.19 In order to clarify the research question and present the background and specific common characteristics of AIOJ/BMD/FDOJ and BRONJ, an extensive literature search was carried out in PubMed Central. In the literature, the terms aseptic-ischemic osteonecrosis of the jaw (AIOJ), bone marrow defects (BMD), and fatty-degenerative osteonecrosis of the jawbone (FDOJ) are used to describe an intramedullary phenomenon with the same pathogenesis, morphology, and pathohistology.

The American Association of Oral and Maxillofacial Surgeons published four staging criteria (at risk, Stage 03).20 Stage 0 is of particular interest in our research as it refers to patients with no clinical evidence of exposed bone, but presence of non-specific symptoms or clinical and/or radiographic abnormalities. The discussion concerning BRONJ is complicated by the fact that there are two clinical forms of BRONJ. The first presents as exposed bone in the maxillofacial region with clinically recognizable necrotic bone that is visibly exposed through the oral mucosa or facial skin, and present for more than 8 weeks, which is referred to as so-called exposed BRONJ.15 The second form of BRONJ is particularly interesting for our investigation; it was recently emphasized that BRONJ does not always appear with necrotic bone visible through a breech in the oral mucosa.21 This form is referred to as non-exposed BRONJ (NE-BRONJ). In the absence of exposed bone, it is characterized by clinical features associated with the jaw, such as unexplained jawbone pain, fistulas/sinus tracts, loose teeth, and swelling.22,23 Diagnosing NE-BRONJ is difficult, as other common jawbone diseases, such as odontogenic infections, may cause similar symptoms and must be excluded. The non-exposed variant may comprise up to one third of all BRONJ cases and is thus not uncommon;24 however, this previously underestimated NE-BRONJ is difficult to accurately diagnose. Recently published papers emphasize that NE-BRONJ has received little attention so far and does not fulfill the current definition of BRONJ.25 Nevertheless, NE-BRONJ belongs to the same disease as exposed BRONJ and should be identified as part of the full spectrum of BRONJ (see the section titled, Case descriptions of AIOJ/BMD/FDOJ, non-exposed BRONJ, and Actinomyces colonization).26

Our investigation requires the identification of the basic immune mechanisms associated with BP administration. Specifically, which mechanism is behind the anti-tumor activity of BPs in cancer patients?

Various studies postulate that BPs change the bone microenvironment around cancer cells, which may prevent cancer cell survival and disease recurrence.27 BPs may also reduce the appearance of disseminated tumor cells. The formation of metastases is complex; mesenchymal stem cells (MSCs) are predominantly found in the bone marrow.28 MSCs may contribute to the formation of metastases through various mechanisms: (1) MSCs are recruited to develop breast tumors where they can enhance the metastatic potential of weakly tumorigenic breast cancer cells;29 (2) MSCs and other bone marrow cells may form a pre-metastatic niche within the specific tissues to which tumor cells metastasize;30 and (3) MSCs are able to maintain the growth and survival of cancer cells in the bone microenvironment where they may contribute to the formation of niches for dormant micrometastases that can later form distant metastases. BPs significantly reduce the ability of MSCs to migrate, thereby reducing the growth and survival of cancer cells.31 Thus, the effects of BPs on MSCs in the bone marrow microenvironment contribute to anti-tumor activity by affecting the ability of MSCs to migrate and develop tumors in pre-metastatic niches. BPs disrupt the interaction between MSCs and breast cancer cells within the bone microenvironment, where BPs may also directly inhibit breast cancer cell growth.

The antiangiogenic effect of BP administration in tumor patients also plays a role in therapy.32 When administered systemically, BPs effectively inhibit angiogenesis. The pronounced antiangiogenic properties of BPs enhance their effectiveness in the treatment of malignant bone diseases. In addition to suppressing RANTES/CCL5 (R/C) expression in MSCs, BP administration plays a role in the treatment of tumor patients.33 Similar to exogenous glucocorticoids and estrogen,34 BPs are ischemic and hypoxia-related stressors of bone health that alter jawbone metabolism, thus leading to osteonecrosis. While tumor-associated BP therapy is currently the heavy weight for bone health, it may accelerate existing, chronic pathophysiological events within the microcirculation of bone marrow compartments in the jaw. BRONJ development is often characterized by a slow start and usually presents with infarcts and thrombosis of small vascular sections of the supplying artery within the medullary canal; these features also correspond to AIOJ/BMD/FDOJ. Myeloid elements (including fat marrow) liquefy and cancellous trabeculae are resorbed, so that individual bone spaces merge and gradually create larger cavities.

If we compare the findings in the sections titled, Bisphosphonates and mesenchymal stem cells and Bisphosphonates and antiangiogenesis to pre-existing AIOJ/BMD/FDOJ, several strikingly common characteristics shared by BRONJ and AIOJ/BMD/FDOJ can be observed that help to answer our research question. In the sections following Bisphosphonates and antitumor therapy, we present the foundations for the development of AIOJ/BMD/FDOJ and draw similarities with the development of BRONJ.

The key function of proinflammatory chemokines R/C in the formation of breast cancer and its metastasis, as well as a possible connection with the intramedullary signaling of R/C overexpression from AIOJ/BMD/FDOJ areas, has been pointed out in previous studies.35,36 The conspicuous overexpression of R/C in little-known BMDs, as found in AIOJ/BMD/FDOJ, has been reported.37,38 R/C overexpression is a regulator of healthy bone metabolism in bone needing repair. The starting point for a typical AIOJ/BMD/FDOJ BMDs is the expression of R/C and its chemokine receptors (CCR5) in both osteoblasts (OBs) and osteoclasts (OCs). Ligands (CCL5) and receptors (CCR5) simultaneously activate autocrine and paracrine mechanisms in the bone.39 One study examined the effects of BPs on human primary OBs and was able to show that the overexpression of proinflammatory R/C from BP-treated OBs also occurs in areas affected by BRONJ.40 The secretion of proinflammatory cytokines interleukin (IL)-8 and R/C increased after 14 days of treatment with the highest dose of BPs.40 The complexity of cytokine control becomes clear at this point. In contrast to the tumor, where BPs in the MSCs reduce R/C expression to such an extent that metastasis is prevented, R/C expression is increased by BPs in OBs. If AIOJ/BMD/FDOJ is already present, it may be assumed that the associated increased R/C secretion is thus further increased by BPs. Specifically, NE-BRONJ may develop as BPs increase the expression of IL-8 and R/C.41 Other researchers have confirmed increases in the secretion of proinflammatory IL-8 and R/C from BP-treated OBs.42 Combined with the lower proliferation rate of OBs and a decrease in their differentiation, higher doses or accumulations of BPs cause undesirable local changes in the bone by increasing the secretion of IL-8 and R/C from OBs. If these findings are applied to BP administration in the context of a chronic, pre-existing AIOJ/BMD/FDOJ area, then such areas may be expected to exhibit increased R/C secretion in response to BPs. This increase may result from the inhibition of OC activity, leading to the development of BRONJ. Figure 1 summarizes the effects of BP administration on the pre-existing physiological derailments associated with tumor and osteoporosis development.

Figure 1 Comparison of the effects of BP administration (+BP) in the context of a tumor (upper part of Figure 1) and pre-existing osteoporosis (lower part of Figure 1). Legend: The red arrows indicate overactivity; the green arrows show reversal following BP administration.

In the literature, the vascular composition of AIOJ/BMD/FDOJ is characterized by the fact that blood flow in the medullary canal is impaired by micro-infarcts, which leads to chronic marrow ischemia.43 BRONJ also shows reduced vascularization in the medullary canal.44 Several publications have shown that ischemic bone diseases such as AIOJ/BMD/FDOJ and BRONJ are of multifactorial origin and emphasize the multiple stroke model as the cause of ischemic bone diseases.45,46 In the orthopedic literature, intensive research conducted on the development of ischemic bone disease in the early stages of the disease process is presented.47 Our aim here is to apply this knowledge not only to extreme forms of the disease, such as osteoradionecrosis and BRONJ, but also to chronic, subclinical, and ischemic forms such as bone marrow edema and AIOJ/BMD/FDOJ, which often progress asymptomatically. Many of these forms are manifestations of both local and systemic risk factors that compromise circulation in the bone marrow, and may also impact on the homeostasis of bone resorption and formation, in addition to BP therapy. The importance of this multifactorial exposure to risk factors for ischemia and the associated causal genetics that are very similar to those in cases of AIOJ/BMD/FDOJ is shown by observing how bone that is exposed to BPs demonstrates minimal OC activity, followed by the deposition of newly formed, thicker bone with reduced vascular supply.48 The resulting mosaic-like pattern of bone remodeling is strikingly similar to that found in Pagets disease, which tends to be associated with the development of osteomyelitis.49 Similar to AIOJ/BMD/FDOJ, the remodeling induced by BPs leaves cavities, otherwise known as cavitations, which leads to both necrosis and unlike that which is found in AIOJ/BMD/FDOJ subsequent infection by colonizing bacteria. Many patients with AIOJ/BMD/FDOJ have inherited prothrombotic tendencies, which is comparable to what is found in patients with idiopathic osteonecrosis of the femoral head (Pagets disease) and includes thrombophilia and hypofibrinolysis.5052 Although a consensus has been reached that ischemic marrow edema is not part of the pathogenesis of BRONJ,53 it is regarded as a typical characteristic of AIOJ/BMD/FDOJ, serving as a precursor to BRONJ development. Systemic antibiotic therapy has limited access to these avascular zones and surgical debridement is usually necessary.

The initial OB situation found in AIOJ/BMD/FDOJ is highly characteristic; under pathological conditions, OBs express R/C chemokines in a non-physiological manner.54,55 The increasing frequency of ONJ and its possible association with high cumulative doses of BPs was investigated in one study, which concluded that high doses of BPs had both OC and OB effects, and thus bone remodeling was inhibited in vivo.56 Other researchers have examined the proliferation, viability, expression, and secretion of bone markers and cytokines/chemokines from primary OBs following exposure to BPs.42 Increased concentrations of proinflammatory cytokines were found in response to BPs. Similarly, increased R/C expression is present in AIOJ/BMD/FDOJ. Following treatment with the highest dose of BPs, the secretions of proinflammatory cytokines IL-8 (P<0.001) and R/C (P<0.001) were significantly increased after 14 days. In addition, the secretion of proinflammatory R/C from OBs exposed to BPs increased. It has also been determined that R/C plays a role in the etiology of the osteolytic changes that are present in AIOJ/BMD/FDOJ.37,57 The aim of another study was to investigate the effect of BPs on human OBs in vitro, while considering RANKL and osteoprotegerin (OPG), both of which mediate OC differentiation.40 OPG increased significantly in the group that received BPs at a dose of 10 M, while RANKL expression decreased significantly with different concentrations of BPs. In summary, exposure to various BP concentrations had a positive effect on OB differentiation, but did not affect proliferation. In contrast, the BP-associated changes in RANKL and OPG production contributed to the suppression of osteoclastic bone resorption. Excess R/C leads to OC inhibition which, in our model, also leads to a disturbance in RANK/RANKL homeostasis (see Figure 2). The chain of reactions that arise from pre-existing AIOJ/BMD/FDOJ and BP administration result in the development of BRONJ in response to the subsequent OB depression; it also leads to increased OC apoptosis. In addition, bone densification takes place following BP administration as a result of increased OB activity. As such, osteonecrosis occurs in the jawbone when BPs are used parenterally. The reasons for these different reactions to BPs have not yet been clarified.

Figure 2 The effects of BP administration and the characteristics of AIOJ/BMD/FDOJ both include depressed alkaline phosphatase (AP) activity with subsequent R/C overexpression. On the one hand, this leads to OC inhibition and, on the other, to RANK/RANKL deactivation, which subsequently causes increased OC apoptosis and depressed OB activity resulting in BRONJ development. Legend: The red arrows indicate deactivation; the green arrows show a reversal of the effect following BP administration.

The first step in tumor necrosis factor alpha (TNF-a)-induced OC genesis occurs in the bone marrow.58 Although mature OCs erode the resorption of the bone as a focal point over the course of months to years, the lifespan of individual OCs is only a few weeks. Thus, mature OCs must be constantly replaced. With respect to OC formation, TNF-a directly stimulates the formation of mature OCs,59,60 and supports and promotes the survival of mature OCs.61 TNF-a increases the survival time of OCs to extend the duration of bone resorption. In the early stages of AIOJ/BMD/FDOJ, the situation for OCs is highly contradictory: the extremely low TNF-a values found in areas of AIOJ/BMD/FDOJ as compared to the values in healthy jawbone samples (as documented in our previous studies) indicate that any inflammatory erosion due to TNF-a supported OC formation is unlikely. Due to reduced TNF-a activation, OC formation in AIOJ/BMD/FDOJ is inhibited, which results in a fatty-degenerative morphology.62

In the same way, BPs inhibit the ability of OCs to resorb bone. They do so by suppressing farnesyl diphosphate synthetase activity, which inhibits OC recruitment and impacts the life expectancy of OCs through increased apoptosis. Where the OC function is excessively inhibited, dying OCs will not be replaced, and the capillary network of the bone will not be maintained, which leads to BRONJ.19 The ability of BPs to regulate bone turnover by suppressing OC activity has led to its widespread use in the treatment of osteoporosis, Pagets disease, humoral hypercalcemia, and in tumors metastasizing to bone.17,63 Several studies have shown the effectiveness of BPs in suppressing OC activity in arthritic bone erosions, which was comparable to the effects of OPG injections.64

The initial alkaline phosphatase (AP) situation in AIOJ/BMD/FDOJ is as follows: AP has an optimum pH in the alkaline range. The pH level of AIOJ/BMD/FDOJ areas, however, is reduced as a consequence of the proinflammatory characteristics of R/C overexpression, resulting in a chronic inflammatory state. AP activity is thus inhibited within the increasingly acidic environment of such areas. Furthermore, BPs increase R/C secretion from OBs, and the acidity of areas affected by AIOJ/BMD/FDOJ, together with an excess of R/C, leads to OC inhibition.65 At the same time, there is also reduced osteogenesis due to the suppression of AP activity,66 as well as the overexpression of R/C that is present in AIOJ/BMD/FDOJ areas and also caused by BP administration. In our model, these two factors led to OC inhibition via disturbed RANK//RANKL homeostasis. In addition, depressed OB activity and increased OC apoptosis result in BRONJ development. While the skeletal bone consolidation that results from BP administration occurs in response to increased OB activity, BRONJ develops in the jawbone when BP is administered parenterally. The reasons for these different responses to BPs have not yet been clarified. If we apply these considerations to an existing AIOJ/BMD/FDOJ area (as shown in Figure 2), then BRONJ and AIOJ/BMD/FDOJ both show suppressed AP activity with subsequent R/C overexpression.67 This leads to OC inhibition and RANK/RANKL deactivation and, subsequently, increased OC apoptosis. Decreased OB activity may ultimately lead to the development of exposed BRONJ.

Despite the similarities detailed in the section titled Osteoimmunological parameters of AIOJ/BMD/FDOJ and BRONJ with the same impact in response to BPs, BRONJ and AIOJ/BMD/FDOJ present two very different clinical pictures; different reactions to BP administration are also likely to occur.

The initial involvement of RANKL in AIOJ/BMD/FDOJ has been described in the literature as follows: pathological increases in levels of R/C and MCP-3 from activated OBs stimulate chemotactic recruitment and RANKL formation of resorptive OCs and aggravate local osteolysis. However, BP administration indirectly inhibits OC maturation by increasing OPG protein secretion and decreases transmembrane RANKL expression in human OBs. Several studies have shown that although BPs do not significantly affect RANKL gene expression, they reduce transmembrane RANKL protein expression in OBs.68,69 This shows that BPs, in addition to directly inhibiting mature OCs, prevent OC recruitment and differentiation by splitting transmembrane RANKL into OBs. OC activation and RANKL activation in areas of AIOJ/BMD/FDOJ, and OC inhibition and RANKL inhibition in BRONJ distinguish these two forms of derailed bone metabolism and thus yield different clinical results. Specifically, imperceptible fatty osteolysis of the marrow structures in AIOJ/BMD/FDOJ and painful BRONJ sequestrum arise as a result. BPs have been shown to downregulate the expression of RANKL, the OC-differentiating factor produced by OBs.70

The initial involvement of OPG in AIOJ/BMD/FDOJ is described in the literature. Since the TNF-a level found in AIOJ/BMD/FDOJ represents only 50% of the TNF-a level in healthy jawbone,36,37 the OPG enzyme that belongs to the TNF family is deactivated. In the resulting osteolysis found in areas of AIOJ/BMD/FDOJ, this leads to reduced RANKL binding and thus results in OC activation. In conclusion, data from previously published studies have suggested that BPs modulate the production of OPG by normal OBs, which may contribute to the inhibition of OC bone resorption.71 As the production of OPG increases with OB maturation, the amplification of OPG by BPs may be linked to OB differentiation via stimulatory BP effects. BPs have been shown to increase the gene expression for the decoy receptor, OPG, in human OBs.71 OPG balance is disturbed in both AIOJ/BMD/FDOJ and BRONJ, albeit in opposite ways. However, the prior imbalance of OPG activity in AIOJ/BMD/FDOJ may increase the effects associated with BP administration.

With respect to the exposed variant of BRONJ, radiographic procedures are required in order to determine the extent to which the degree of ossification has increased.72 However, the existence of this variant of BRONJ is clinically evident. In contrast, the non-exposed BRONJ variant and AIOJ/BMD/FDOJ are associated with very similar problems in terms of diagnostic imaging. As with AIOJ/BMD/FDOJ, the prevalence of this variant of BRONJ is largely underestimated as the disease is often underdiagnosed and under-reported.73 Studies have shown that almost a quarter of patients with BRONJ remain undiagnosed.74

The initial histopathological presentation of AIOJ/BMD/FDOJ found in the literature is as follows: Bouquot describes these bone modeling disorders as ischemic osteonecrosis, which is a bone disease characterized by the degeneration and death of marrow and bone due to a slow or abrupt decrease in marrow blood flow.75 Clumps of coalesced, liquefied fat (oil cysts) may be seen. Bone death is represented by a focal loss of OCs. Dark masses of calcific necrotic detritus may often be present.75 The histopathological features of AIOJ/BMD/FDOJ include necrotic adipocytes and fibrosis, but an almost complete absence of inflammatory cells.76 Additional research has shown the role of aseptic necrosis following injury or drug therapy in the pathophysiology of BRONJ. Aseptic bone necrosis, as found in AIOJ/BMD/FDOJ, has been reported as a manifestation of selected systemic diseases and also documented following operations, trauma, and immunosuppressive therapy at the site of BRONJ.77,78 The development of aseptic necrosis has been documented in the upper and lower jaw, particularly following osteotomies.79,80 Researchers have observed a relationship between oral BP use and non-specific aseptic osteonecrosis among a cohort of older cardiovascular patients.81 Other researchers have identified necrotic liquefaction, which often extend to large areas of the jaw, especially within BRONJ lesions of cancer patients, as shown using digital volume tomography (DVT)/cone beam computed tomography (CBCT).82 Research has been published on BRONJ samples that were characterized by low to moderate inflammation.83 This is in accordance with other reports of histopathological analyses of BRONJ samples.48,78,8486 Bone samples from BRONJ patients were investigated by microscopy and the presence of inflammatory infiltrates in the bone tissues was not observed.87 These studies have demonstrated that aseptic necrosis, a lack of inflammatory reactions, and empty OC lacunae are common histopathological features of AIOJ/BMD/FDOJ and BRONJ.

The diagnostic difficulties associated with BRONJ and AIOJ/BMD/FDOJ present another common feature. In order to diagnose BRONJ with imaging procedures, the Task Force Report of the American Society for Bone and Mineral Research highlights that the differential diagnosis of BRONJ should exclude other common intraoral diseases such as periodontitis, gingivitis, infectious osteomyelitis, osteoradionecrosis, neuralgia-inducing cavitational osteonecrosis (NICO), bone tumors, and metastases.15 The authors of the report thus rule out an etiological equation for diagnosing NICO and BRONJ. The current review is focused on the potential role of imaging techniques in the diagnosis of the early stages of BRONJ. A combination of clinical and radiological symptoms suggest that, while not specific to BRONJ, they may collectively be more comprehensive and representative of the bone disease process.2 The American Association of Maxillofacial Surgery accepts the use of imaging techniques when detecting BRONJ during presurgical evaluation.72 It is important for the BRONJ patient that various imaging methods be examined critically prior to being adopted for the early detection and diagnosis of BRONJ.

Figure 3 Left panel shows jawbone area 18; hematoxylin and eosin staining, magnification 200. The lower half of the image illustrates eosinophilic bone substance with empty osteocyte cavities corresponding to devitalized bone sequestrum. Middle part of the left panel: Highly irregular trabecular surfaces with a wide edging comprised of Actinomyces colonies surrounded by a wall of leukocytes. Upper part of left panel: Fibrin particles and individual lymphocytes. Right panel: Actinomyces granules visualized in a PAS reaction; the red color represents a broad band of granules in the middle. The lower edge of the right panel images once again shows a bone sequestrum and typically empty osteocyte lacunae. Diagnosis: Aseptic bone necrosis with Actinomyces colonization.

The histopathological changes in necrotic bone may be visualized with MRI scans, as with CBCT/DVT. The images detect progressive cell death and the repair response (ie, edema). As the fat cells in normal bone marrow provide high signal intensity, it may be assumed that signal changes evident in the marrow are related to the death of fat cells. Necrotic adipocytes are a morphological characteristic of AIOJ/BMD/FDOJ.76 Following the application of a contrast agent, areas of ischemia may be identified as non-enhancing regions. Cases in which fibrosis and sclerosis of the bone occur may also result in lower signal intensity. Nevertheless, the currently available data on MRI results for BRONJ are limited,96 as are those related to AIOJ/BMD/FDOJ. Studies showed positron-emission tomography (PET) as a sensitive method for diagnosis of BRONJ. Thus, PET could be useful for evaluating the severity of BRONJ.97

2D-OPG is used to identify osteopathies of the jawbone. However, this imaging technique fails to show AIOJ/BMD/FDJ areas, thus generating false-negative findings. As a result, AIOJ/BMD/FDOJ have been highly neglected in dentistry and medicine.98 Therefore, transalveolar ultrasound sonography (TAU) appears to be necessary as an additional imaging technique in order to improve the diagnosis of AIOJ/BMD/FDOJ.99,100 A newly developed TAU device (TAU-n) measures sound velocity attenuation when the bone marrow has been penetrated. An ultrasound transmitter is placed over the jaw area and a thumbnail-sized receiver is placed inside the mouth. To obtain reproducible results when measuring bone density, the transmitter and receiver are arranged in a coplanar and fixed position. The parts of the receiving unit are placed inside a patients mouth, the acoustic coupling between those parts and the alveolar ridge is performed with the aid of a semi-solid gel (Figure 3). With the receiver containing 91 piezoelectric fields, sound waves are registered and converted into a color graph of the corresponding areas of bone density (Figure 4).On the graphic visualization, green indicates healthy, dense, and solid bone, yellow indicates the presence of ischemic metabolism, and orange and red highlight areas of AIOJ/BMD/FDOJ presence.101

Figure 4 Left panel shows positioning of transmitter (outside) and receiver (enoral) in the lower jaw; the red band marks the cheek. Right panel shows the transmitter (in blue at the right) and receiver (in green at the left) in a fixed coplanar position (blue bar connecting the transmitter and receiver); semi-solid gel pads between the transmitter and the cheek on the outside of the mouth and between receiver and the alveolar ridge in the enoral position; trans-alveolar ultrasonic impulse from the transmitter to receiver (arrows in blue).

Figure 5 Inconspicuous 2D-OPG findings (left panel); suspected osteolytic processes in areas 1719 in the sagittal section of the image using DVT (right panel). Lower panel: TAU measurement from region 17 to retromolar region 19. Legend: Green areas indicate normal bone density; yellow, orange, and red areas show decreasing bone density until complete osteolysis is reached.

A clinical case of a 55-year-old patient with prostate carcinoma who was treated with parenteral BPs received an X-ray diagnosis of non-exposed BRONJ with normal intraoral findings in the right upper jawbone from area 17 to retromolar area 19. While 2D-OPG of area 18/19 showed no suspicious findings, the CBCT/DVT image demonstrated ossification irregularities and partial cavities that resembled AIOJ/BMD/FDOJ. The development and progression of BRONJ could not be reliably determined by reference to these images and it was not possible to make a differential diagnosis. In contrast, TAU-n images clearly indicated osteolysis (see Figure 4, below). The postoperative light microscopy findings from area 18/19 showed marrow with adipose tissue, significant fibrillar and myxoid degeneration of adipocytes, individual lymphocytes, and mast cells; however, no florid inflammation was observed. These are the typical histological features of AIOJ/BMD/FDOJ.76 It is worth noting, however, that there was a large bone sequestrum with empty OC cavities, highly irregular trabecular surfaces, and empty marrow spaces, with Actinomyces colonization (Figure 3).

Several reviews have indicated that light microscopy examinations were able to detect that 68.8% of BRONJ cases featured Actinomyces colonization.32 Anaerobic Actinomyces has long been associated with necrotic bone findings in BRONJ lesions.102 Actinomyces colonization is thus a top priority as a possible pathological trigger with respect to BRONJ. Since we have not identified bacterial colonization in areas of AIOJ/BMD/FDOJ in our own studies,103 an accompanying secondary Actinomyces colonization seems to be an additional prerequisite for the development of BRONJ from an area of AIOJ/BMD/FDOJ in response to BP administration.

Table 1 displays all studies and their impact on the research question based on the inclusion and exclusion criteria in literature review.

Table 1 The Table Displays the Criteria for Inclusion of Specific Manuscripts in Our Research. Exclusion Criteria Were Unspecific Reviews Concentrating on Exposed BRONJ Only

Can hitherto little-known, yet according to our clinical experience37,76 epidemiologically widespread AIOJ/BMD/FDOJ represent cofactors in the development of BRONJ? The development of biological processes takes place in different stages and during various phases of transition. This also seems to be the case for BRONJ, as the exposed form found in the maxillofacial region represents the final, late-stage form of the NE-BRONJ variant. The focus of our study is thus on the early stage of BRONJ (Stage 0) without exposed bone, as based on the recommendations of the American Association of Oral and Maxillofacial Surgeons.5,20,104 Our hypothesis considers the NE-BRONJ variant as one stage of development featuring an unrecognized BMD that is characteristic of AIOJ/BMD/FDOJ and amplified by BP administration. The cumulative effects of BPs on pre-existing AIOJ/BMD/FDOJ support this premise. The relationship between AIOJ/BMD/FDOJ and the administration of BPs (as shown in Figure 6) leads, etiologically, to the non-exposed BRONJ variant, which is less clearly described in the literature than the late-stage form of BRONJ, and also results in considerable oral impairment.

Figure 6 Overview of the individual osteoimmunological signal cascades present in AIOJ/BMD/FDOJ and their conversion or amplification following BP administration, resulting in the development of BRONJ. Legend: A pair of arrows, one red and one green, indicates the reinforcement or, in one instance, the reversal of the typical overexpression or inhibition found in AIOJ/BMD/FDOJ following BP administration.

As BPs and AIOJ/BMD/FDOJ exert the same effects, resulting in the hyperfunctioning of R/C expression, OB activity, hypoxia/ischemia, and the inhibition of OC activity, vascularization, and AP activity, AIOJ/BMD/FDOJ may be regarded as a prerequisite to the formation of BRONJ. Changes in silent AIOJ/BMD/FDOJ processes, including strongly inhibited OC production, reduced RANKL activity, and increased OPG activity, appear to induce the occurrence of BRONJ. Figure 7 presents a hypothetical three-step model detailing the basic stages for the development of BRONJ at AIOJ/BMD/FDOJ areas. Regions with fatty-degenerative changes may be the focal point for the subsequent development of BRONJ, as such changes may constitute an additional risk factor. This is consistent with the hypothesis described in the literature, whereby bone necrosis precedes clinically evident ONJ that is exposed through the oral mucosa.78,105 Regions featuring subclinical changes and necrotic bone may represent significant risk factors in the development of BRONJ.104 Further, it is known that patients at each stage exhibit a very different bone composition.104

Figure 7 Three-step model for the development of BRONJ beginning with undetected AIOJ/BMD/FDOJ followed by the development of the NE-BRONJ variant, and finally by BRONJ.Notes: Exposed bone BNOJ (left panel). Bony sequestrum BRONJ (right panel). Figure courtesy of Professor J Bouquot.

The prevention of BRONJ is of paramount importance and has been repeatedly emphasized.106108 Thus, BPs should not be regarded as the sole cause of osteonecrosis. The results of this study indicate that unresolved areas of wound healing at extraction sites especially in former wisdom tooth areas may directly contribute to the pathogenesis of BRONJ. Other research has already described the involvement of the jaw in BRONJ as opposed to other bone sites.109 This may be because BPs are preferentially deposited in bones with high turnover rates such as the jawbone. The jawbone also presents with hidden conditions that according to our hypothesis share common characteristics with those found in AIOJ/BMD/FDOJ. Under the influence of BPs, areas of AIOJ/BMD/FDOJ may develop the pathological features of BRONJ. Efforts to prevent BRONJ, therefore, should not ignore the fact that BRONJ and AIOJ/BMD/FDOJ share similar osteoimmunological characteristics with respect to amplifying or reversing derailed signal cascades. Since AIOJ/BMD/FDOJ represent chronic, subclinical states, the sudden formation of BRONJ may be interpreted as a subsequent acute event. The early detection of BRONJ (as well as AIOJ/BMD/FDOJ) using X-ray techniques appears to be difficult. A new risk-benefit analysis should be considered: Patients should be screened for hidden oral risk factors, such as AIOJ/BMD/FDOJ. Thus, TAU may be used to measure bone density and fill this diagnostic gap. When parenteral BP therapy is administered, periodontal prophylaxis and tooth restoration should take precedence;110,111 furthermore, AIOJ/BMD/FDOJ should be diagnosed first, preferably (and accurately) with TAU-n, and then surgically eliminated. The formation of difficult-to-treat BRONJ could be avoided in certain cases if the exacerbation of pre-existing areas of AIOJ/BMD/FDOJ is prevented before initiating anti-tumorigenic BP therapy. Surgical opening of the cortex, removal of ischemic marrow, and accompanying wound care represent the only way to address cases of AIOJ/BMD/FDOJ.112 Consultation with an oncologist is mandatory, as the oncologist may insist on radiation therapy and the prevention of osteoradionecrosis of the jawbones via tooth restoration. To the best of our knowledge, we have highlighted, for the first time, the possible impact chains flowing from AIOJ/BMD/FDOJ and leading to the development of NE-BRONJ and further to exposed BRONJ. We also support the hypothesis presented herein with scientific data from the available literature. Due to the lack of clinical studies investigating these impact chains, multiple studies are necessary to elucidate the hypothesized relationships.

AIOJ, aseptic-ischemic osteonecrosis of the jawbone; BMD, bone marrow defects; BRONJ, bisphosphonate (BP)-related osteonecrosis of the jaw; CBCT, cone beam computed tomography; CCL5, chemokine (C-C motif) ligand 5; DVT, digital volume tomography; FDOJ, fatty-degenerative osteonecrosis/osteolysis of the jawbone; HU, hounsfield units; OPG, orthopantomogram; R/C, RANTES/CCL5; RANTES, regulated on activation, normal T cell expressed and secreted; TAU, transalveolar ultrasonography; TAU-n, new transalveolar ultrasonography device.

Hereby we confirm that written informed consent has been provided by the patient to have the case details and any accompanying images published. The data were collected as part of the normal everyday medical care of the patients and evaluated retrospectively. Institutional approval was not required to publish the case details.

English language editing of this manuscript was provided by Journal Prep Services. Additional English language editing was provided by Natasha Gabriel.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The corresponding author, Johann Lechner, is the holder of a patent used in the TAU-n apparatus and its associated software and reports a patent CaviTAU licensed to Dr. Johann Lechner. Bernd Zimmermann is an employee of QINNO. The authors report no other potential conflicts of interest for this work.

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42. Krger TB, Herlofson BB, Landin MA, Reseland JE. Alendronate alters osteoblast activities. Acta Odontol Scand. 2016;74:550557. doi:10.1080/00016357.2016.1217041.

43. Bouquot J, McMahon R The histopathology of chronic ischemic bone disease (ON) parameters and disease classification. Tucson, Arizona: Proceedings of the Annual Meeting of the American Association of Oral & Maxillofacial Pathology; 2010.

44. Assael LA. New foundations in understanding osteonecrosis of the jaws. J Oral Maxillofacial Surg. 2004;62:125126. doi:10.1016/j.joms.2003.11.009.

45. Kenzora J, Glimcher M. Accumulative cell stress: the multifactorial etiology of idiopathic osteonecrosis. Orthop Clin North Am. 1985;16:669679.

46. Schoutens A, Arlet J, Gardeniers J, Hughes S, editors. Bone Circulation and Vascularization in Normal and Pathological Conditions. New York, NY: Plenum Press; 1993.

47. Arlet J, Mazieres B. Bone Circulation and Bone Necrosis. Heidelberg, Germany: Springer-Verlag; 1990.

48. Favia G, Pilolli GP, Maiorano E. Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone. 2009;45:406413. doi:10.1016/j.bone.2009.05.008.

49. Paparella ML, Brandizzi D, Santini-Araujo E, Cabrini RL. Histopathological features of osteonecrosis of the jaw associated with bisphosphonates. Histopathology. 2012;60:514516. doi:10.1111/j.1365-2559.2011.04061.x.

50. Gruppo R, Glueck CJ, Mcmahon RE, et al. The pathophysiology of alveolar osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. J Lab Clin Med. 1996;127:481488. doi:10.1016/S0022-2143(96)90065-7.

51. Glueck CJ, McMahon RE, Bouquot J, et al. Thrombophilia, hypofibrinolysis, and alveolar osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol. 1996;81:557566. doi:10.1016/S1079-2104(96)80047-3.

52. Glueck C, Freiberg R, Gruppo R. Osteonecrosis: Etiology, Diagnosis, and Treatment. Rosemont, IL: American Academy of Orthopaedic Surgeons; 1997.

53. Gabriel H, Fitzgerald SW, Myers MT, Donaldson JS, Poznanski AK. MR imaging of hip disorders. RadioGraphics. 1994;14:763781. doi:10.1148/radiographics.14.4.7938767.

54. Votta BJ, White JR, Dodds RA, et al. CKbeta-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues. J Cell Physiol. 2000;183:196207. doi:10.1002/(SICI)1097-4652(200005)183:2<96::aid-jcp6>3.0.CO;2-8.

55. Lisignoli G, Toneguzzi S, Grassi F, et al. Different chemokines are expressed in human arthritic bone biopsies: IFN- and IL-6 differently modulate IL-8, MCP-1 AND RANTES production by arthritic osteoblasts. Cytokine. 2002;20:231238. doi:10.1006/cyto.2002.2006.

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[Full text] Osteonecrosis of the Jaw Beyond Bisphosphonates: Are There Any Unknown | CCIDE - Dove Medical Press

Bone Marrow Stem Cells Comments Off on [Full text] Osteonecrosis of the Jaw Beyond Bisphosphonates: Are There Any Unknown | CCIDE – Dove Medical Press | January 22nd, 2021

BrainStorm Cell Therapeutics has announced that its NurOwn (MSC-NTF cell) derived exosomes provided significant improvement in lung function and histology in an acute respiratory distress syndrome (ARDS) mouse model, in a preclinical study.

Mesenchymal stem cell (MSC)-derived exosomes can penetrate deep into tissues and deliver immunomodulatory molecules effectively.

A type of respiratory failure, ARDS is linked to Covid-19 and is mediated by dysregulated cytokine production.

Intratracheal administration of NurOwn derived exosomes provided a statistically significant reduction in lung disease severity score, the study data showed.

Furthermore, improvements in lipopolysaccharide (LPS)-induced ARDS markers like lung function, fibrin presence, neutrophil accumulation, cytokine expression and oxygenation levels in the blood, were observed.

These improvements were significantly superior to those noticed following nave MSC-derived exosome administration.

BrainStorm Research and Development vice-president Dr Revital Aricha said: These exciting preclinical data suggest that NurOwn derived exosomes have the potential to treat Covid-19-induced ARDS or other severe respiratory complications and that they are more effective than exosomes isolated from nave MSCs at combatting the various symptoms of the syndrome.

This publication in a highly regarded journal provides important validation for the scientific advances and significance of BrainStorms preclinical research programs, including on our exosome-based technology platform.

The NurOwn technology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders.

GlobalData's TMT Themes 2021 Report tells you everything you need to know about disruptive tech themes and which companies are best placed to help you digitally transform your business.

MSC-NTF cells are made from autologous, bone marrow-derived MSCs expanded and separated ex vivo.

Brainstorm CEO Chaim Lebovits said: While our primary focus is on advancing NurOwn towards regulatory approval in ALS, we continue to evaluate the potential of our exosome-based platform to address unmet medical needs.

In December 2019, the company received a recommendation from the independent Data Safety Monitoring Board (DSMB) to continue the Phase II clinical trial of NurOwn in progressive multiple sclerosis patients.

Global Real Time Tracking and Monitoring Solutions for Clinical trials

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BrainStorm's Covid-19 ARDS treatment improves lung function in study - Clinical Trials Arena

Bone Marrow Stem Cells Comments Off on BrainStorm’s Covid-19 ARDS treatment improves lung function in study – Clinical Trials Arena | January 22nd, 2021

This article was originally published here

Stem Cell Res Ther. 2021 Jan 13;12(1):58. doi: 10.1186/s13287-020-02110-x.

ABSTRACT

INTRODUCTION: Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment.

METHODS: For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis.

RESULTS: Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups.

CONCLUSIONS: Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.

PMID:33436054 | DOI:10.1186/s13287-020-02110-x

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Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy - DocWire News

Bone Marrow Stem Cells Comments Off on Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy – DocWire News | January 14th, 2021

A SHIPYARD worker has potentially saved a stranger's life after donating his stem cells to a person in desperate need.

Brad Lawson, from Walney, first signed up to be a stem cell donor six years ago after an event at his college.

Stem cells are cells with the potential to develop into many different types of cells in the body.

Every 14 minutes, someone is diagnosed with blood cancer such as leukaemia.

For many, a bone marrow or blood stem cell transplant is their only chance.

They need cells from a healthy person with the same tissue type to replace and repair their own damaged cells.

About 30 per cent of people in need can find a suitable donor in their family but the other 70 per cent rely on a stranger to save their lives.

This is what prompted Mr Lawson to travel hundreds of miles to London to give his much-needed donation.

The 23-year-old said: "I first signed onto the register six years ago and hadn't thought much about it since.

"Then I was shocked to get a phone call the other week to say they'd matched a patient with my stem cells.

"It's quite rare to match with someone - it's only one in 800 people so I knew I had to help."

Mr Lawson travelled down to London where he underwent peripheral blood stem cell collection.

The process involves having a course of injections prior to collection to stimulate the bone marrow and increase the number of stem cells and white blood cells in the blood.

He said: "I had no hesitation about going down there when I got the call. When you sign up, you need to be fully committed if you do get a call.

"This could be someone's chance of survival and I would never pull out of something like that.

"The process was actually really easy. It takes about five hours and isn't painful at all.

"I absolutely hate needles and didn't find it painful at all."

Mr Lawson said it felt 'rewarding' to know his donation could have possibly saved a stranger's life.

"You could potentially give someone the chance to survive by signing up," he said.

"It's an amazing thing to do which could seriously make a difference.

"I may be in that position one day where I desperately need stem cells and would like to think someone out there would help me.

"Donations literally saves lives. It's a really rewarding thing to do to be able to help someone in this way."

Mr Lawson is urging the public to sign up to the register.

"Only about two per cent of people in the UK are actually on the register," he said.

"I'm telling everyone to sign up and raise awareness of stem cell donation.

"The more people we can get to sign up, and save lives, the better."

To register, visit: http://www.dkms.org.uk/en/register-now.

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Shipyard worker Brad Lawson from Walney may have saved a stranger's life with his stem cell donation - NW Evening Mail

Bone Marrow Stem Cells Comments Off on Shipyard worker Brad Lawson from Walney may have saved a stranger’s life with his stem cell donation – NW Evening Mail | January 14th, 2021

Full TitleCord Blood Transplantation in Children and Young Adults with Hematologic Malignancies and Non-Malignant DisordersPurpose

The transplantation of stem cells from umbilical cord blood is a treatment for some blood cancers and non-cancerous blood or metabolic disorders. Patients routinely receive high doses of chemotherapy and sometimes radiation before receiving the stem cells to help make room in the bone marrow for new blood stem cells to grow, prevent the body from rejecting the transplanted cells, and help kill any abnormal blood cells in the body. However, the combination of these treatments can have serious side effects.

Researchers are doing this study to find out whether a combination of the chemotherapy drugs clofarabine, fludarabine, and busulfan (without radiation) is a safe and effective treatment for children and young adults receiving cord blood transplants for blood cancers or non-cancerous blood or metabolic disorders. These three drugs are given intravenously (by vein).

To be eligible for this study, patients must meet several criteria, including but not limited to the following:

For more information about this study and to inquire about eligibility, please contact 1-833-MSK-KIDS.

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A Study of Cord Blood Transplantation in Children and Young Adults with Blood Cancers and Non-Cancerous Blood Disorders - On Cancer - Memorial Sloan...

Bone Marrow Stem Cells Comments Off on A Study of Cord Blood Transplantation in Children and Young Adults with Blood Cancers and Non-Cancerous Blood Disorders – On Cancer – Memorial Sloan… | January 14th, 2021

The Adipose Derived Stem Cell Therapy Market Research Report is a resource, which provides current as well as upcoming technical and financial details of the industry to 2027. This report gives you so important and essentials data of Market size, share, trends, Growth, applications, forecast and cost analysis. Delivery development in North America, China, Europe, and South East Asia, Japan as well as in the Globe. The report proves to be indispensable when it comes to market definition, classifications, applications and engagements. The market report also computes the market size and revenue generated from the sales. The industry analysis report presents the key statistics on the market status of global and regional manufacturers and also acts as a valuable source of leadership and direction. What is more, theAdipose Derived Stem Cell Therapy market report analyses and provides historic data along with the current performance of the market

Adipose derived stem cells (ADSCs) are stem cells derived from adipocytes, and can differentiate into variety of cell types. ADSCs have multipotency similar to bone marrow mesenchymal stem cells, thus ADSCs substitute for bone marrow as a source of stem cells. Numerous manual and automatic stem cell separation procedures are adopted in order to separate adipose stem cells (ASCs) from adipose tissue. Flow cytometry can also be used to isolate ADSCs from other stem cells within a cell solution.

This Press Release will help you to Know the Volume, growth with Impacting Trends. Get SAMPLE PDF (Including Full TOC, Table & Figures) at:

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Global Adipose Derived Stem Cell Therapy Market competition by Top Key Players: BioRestorative Therapies, Inc., Celltex Therapeutics Corporation, Antria, Inc., Cytori Therapeutics Inc., Intrexon Corporation, Mesoblast Ltd., iXCells Biotechnologies, Pluristem Therapeutics, Inc., Thermo Fisher Scientific, Inc., Tissue Genesis, Inc., Cyagen US Inc., Celprogen, Inc., and Lonza Group, among others.

Adipose Derived Stem Cell Therapy Market section by Region:

The Middle East and Africa North AmericaSouth AmericaEuropeAsia-Pacific

Segmentation: The report has been separated into different categories, such as product type, application, end user, and region. Every segment is evaluated based on the CAGR, share and growth potential. In the regional analysis, the report highlights the prospective region, which should generate opportunities in the global Adipose Derived Stem Cell Therapy market in the years to come. This segmented analysis will surely prove to be a useful tool for readers, stakeholders and market participants to get a full picture of the Adipose Derived Stem Cell Therapy global market and its growth potential in the years to come.

TheAdipose Derived Stem Cell TherapyMarket report offers a plethora of insights which include:

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Important Information that can be extracted from the Report:

Assessment of the COVID-19 impact on the growth of the Adipose Derived Stem Cell Therapy MarketSuccessful market entry strategies formulated by emerging market playersPricing and marketing strategies adopted by established market playersCountry-wise assessment of the Adipose Derived Stem Cell Therapy Market in key regionsYear-on-Year growth of each market segment over the forecast period 2026

TheAdipose Derived Stem Cell TherapyMarket report considers the following years to predict market growth:

The GlobalAdipose Derived Stem Cell TherapyMarket is displayed in 13 Chapters:

Chapter 1: Market Overview, Drivers, Restraints and OpportunitiesChapter 2: Market Competition by ManufacturersChapter 3: Production by RegionsChapter 4: Consumption by RegionsChapter 5: Production, By Types, Revenue and Market share by TypesChapter 6: Consumption, By Applications, Market share (%) and Growth Rate by ApplicationsChapter 7: Complete profiling and analysis of ManufacturersChapter 8: Manufacturing cost analysis, Raw materials analysis, Region-wise manufacturing expensesChapter 9: Industrial Chain, Sourcing Strategy and Downstream BuyersChapter 10: Marketing Strategy Analysis, Distributors/TradersChapter 11: Market Effect Factors AnalysisChapter 12: Market ForecastChapter 13:Adipose Derived Stem Cell Therapy Research Findings and Conclusion, Appendix, methodology and data source

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Adipose Derived Stem Cell Therapy Market Analysis and Forecast, 2020-2026 Coherent Market Insights | BioRestorative Therapies, Inc., Celltex...

Bone Marrow Stem Cells Comments Off on Adipose Derived Stem Cell Therapy Market Analysis and Forecast, 2020-2026 Coherent Market Insights | BioRestorative Therapies, Inc., Celltex… | January 14th, 2021

This article was originally published here

Cancers (Basel). 2021 Jan 10;13(2):E226. doi: 10.3390/cancers13020226.

ABSTRACT

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression.

PMID:33435153 | DOI:10.3390/cancers13020226

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Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma - DocWire News

Bone Marrow Stem Cells Comments Off on Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma – DocWire News | January 14th, 2021

Stem cell assay refers to the procedure of measuring the potency of antineoplastic drugs, on the basis of their capability of retarding the growth of human tumor cells. The assay consists of qualitative or quantitative analysis or testing of affected tissues and tumors, wherein their toxicity, impurity, and other aspects are studied.

With the growing number of successful stem cell therapy treatment cases, the global market for stem cell assays will gain substantial momentum. A number of research and development projects are lending a hand to the growth of the market. For instance, the University of Washingtons Institute for Stem Cell and Regenerative Medicine (ISCRM) has attempted to manipulate stem cells to heal eye, kidney, and heart injuries. A number of diseases such as Alzheimers, spinal cord injury, Parkinsons, diabetes, stroke, retinal disease, cancer, rheumatoid arthritis, and neurological diseases can be successfully treated via stem cell therapy. Therefore, stem cell assays will exhibit growing demand.

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Another key development in the stem cell assay market is the development of innovative stem cell therapies. In April 2017, for instance, the first participant in an innovative clinical trial at the University of Wisconsin School of Medicine and Public Health was successfully treated with stem cell therapy. CardiAMP, the investigational therapy, has been designed to direct a large dose of the patients own bone-marrow cells to the point of cardiac injury, stimulating the natural healing response of the body.

Newer areas of application in medicine are being explored constantly. Consequently, stem cell assays are likely to play a key role in the formulation of treatments of a number of diseases.

Global Stem Cell Assay Market: Overview

The increasing investment in research and development of novel therapeutics owing to the rising incidence of chronic diseases has led to immense growth in the global stem cell assay market. In the next couple of years, the market is expected to spawn into a multi-billion dollar industry as healthcare sector and governments around the world increase their research spending.

The report analyzes the prevalent opportunities for the markets growth and those that companies should capitalize in the near future to strengthen their position in the market. It presents insights into the growth drivers and lists down the major restraints. Additionally, the report gauges the effect of Porters five forces on the overall stem cell assay market.

Global Stem Cell Assay Market: Key Market Segments

For the purpose of the study, the report segments the global stem cell assay market based on various parameters. For instance, in terms of assay type, the market can be segmented into isolation and purification, viability, cell identification, differentiation, proliferation, apoptosis, and function. By kit, the market can be bifurcated into human embryonic stem cell kits and adult stem cell kits. Based on instruments, flow cytometer, cell imaging systems, automated cell counter, and micro electrode arrays could be the key market segments.

In terms of application, the market can be segmented into drug discovery and development, clinical research, and regenerative medicine and therapy. The growth witnessed across the aforementioned application segments will be influenced by the increasing incidence of chronic ailments which will translate into the rising demand for regenerative medicines. Finally, based on end users, research institutes and industry research constitute the key market segments.

The report includes a detailed assessment of the various factors influencing the markets expansion across its key segments. The ones holding the most lucrative prospects are analyzed, and the factors restraining its trajectory across key segments are also discussed at length.

Global Stem Cell Assay Market: Regional Analysis

Regionally, the market is expected to witness heightened demand in the developed countries across Europe and North America. The increasing incidence of chronic ailments and the subsequently expanding patient population are the chief drivers of the stem cell assay market in North America. Besides this, the market is also expected to witness lucrative opportunities in Asia Pacific and Rest of the World.

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Global Stem Cell Assay Market: Vendor Landscape

A major inclusion in the report is the detailed assessment of the markets vendor landscape. For the purpose of the study the report therefore profiles some of the leading players having influence on the overall market dynamics. It also conducts SWOT analysis to study the strengths and weaknesses of the companies profiled and identify threats and opportunities that these enterprises are forecast to witness over the course of the reports forecast period.

Some of the most prominent enterprises operating in the global stem cell assay market are Bio-Rad Laboratories, Inc (U.S.), Thermo Fisher Scientific Inc. (U.S.), GE Healthcare (U.K.), Hemogenix Inc. (U.S.), Promega Corporation (U.S.), Bio-Techne Corporation (U.S.), Merck KGaA (Germany), STEMCELL Technologies Inc. (CA), Cell Biolabs, Inc. (U.S.), and Cellular Dynamics International, Inc. (U.S.).

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Stem Cell Assay Market | Know the aspects that will serve as game-changers for the market - BioSpace

Bone Marrow Stem Cells Comments Off on Stem Cell Assay Market | Know the aspects that will serve as game-changers for the market – BioSpace | January 14th, 2021

Gosselies, Belgium and Modena, Italy, 14January 2021, 7am CET BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, and Rigenerand SRL, the biotech company that both develops and manufactures medicinal products for cell therapy applications, primarily for regenerative medicine and oncology, today announce the signing of a first agreement for a process development partnership.

Allogeneic mesenchymal stem cell (MSC) therapies are currently being developed at an incredible pace and are evaluated in numerous clinical studies covering diverse therapeutic areas such as bone and cartilage conditions, liver, cardiovascular and autoimmune diseases in which MSCs could have a significant positive effect. Advances in process development to scale up these therapies could have major impacts for both their approval and commercial viability. This will be essential to bring these therapies to market to benefit patients as quickly as possible, said Miguel Forte, CEO, Bone Therapeutics. Hence, whilst Bone Therapeutics is driving on its existing clinical development programs, we have signed a first formal agreement with Rigenerand as a fellow MSC-based organization. This will result in both companies sharing extensive expertise in the process development and manufacturing of MSCs and cell and gene therapy medicinal products. Bone Therapeutics also selected Rigenerand to partner with for their additional experience with wider process development of advanced therapy medicinal products (ATMPs), including the conditioning and editing of MSCs. Rigenerand was founded by Massimo Dominici, a world opinion leader in the cell therapy with an unparalleled MSC expertise and knowledge.

The scope of collaborations between Bone Therapeutics and Rigenerand aims to focus on different aspects of product and process development for Bone Therapeutics expanding therapeutic portfolio. Rigenerand will contribute to improving the processes involved in the development and manufacture of Bone Therapeutics MSC based allogeneic differentiated cell therapy products as they advance towards patients. The first collaboration between the two organizations will initially focus on augmented professional bone-forming cells cells that are differentiated and programmed for a specific task. There is also potential for Bone Therapeutics to broaden its therapeutic targets and explore new mechanisms of action with potential gene modifications for its therapeutic portfolio.

In addition to Rigenerands MSC expertise, Bone Therapeutics also selected Rigenerand as a partner for Rigenerands GMP manufacturing facility. This facility, situated in Modena, Italy, has been designed to host a number of types of development processes for ATMPs. These include somatic, tissue engineered and gene therapy processes. These multiple areas of Rigenerand capabilities enable critical development of new processes and implementation of the gene modification of existing processes. In addition, Rigenerand has built considerable experience in cGMP manufacturing of MSC-based medicinal products, including those that are genetically modified.

Process development and manufacturing is a key part of the development for ATMPs internationally. Navigating these therapies through the clinical development phase and into the market requires a carefully considered process development pathway, said Massimo Dominici, scientific founder, Rigenerand, professor of medical oncology, and former President of the International Society for Cell & Gene Therapy (ISCT). This pathway needs to be flexible, as both the market and materials of these therapies continues to evolve alongside an improved clinical efficacy.

Rigenerand will offer considerable input from its experience of MSC-based therapies to enable Bone Therapeutics to keep and further accelerate the pace in development of the product processes of its MSC based allogeneic differentiated cell therapy as they advance towards patients, said Giorgio Mari, CEO, Rigenerand. We will continue to use our MSC expertise in the development of Rigenerands own products, as well as in process development and manufacturing cell and gene therapies for partner organizations across the globe.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in Phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid - a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive Phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company has initiated patient recruitment for the Phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

About Rigenerand

Rigenerand SRL is a biotech company that both develops and manufactures medicinal products for cell therapy applications, primarily for regenerative medicine and oncology and 3D bioreactors as alternative to animal testing for pre-clinical investigations.

Rigenerand operates through three divisions:

Rigenerand is developing RR001, a proprietary ATMP gene therapy medicinal product for the treatment of pancreatic ductal adenocarcinoma (PDAC). RR001 has been granted an Orphan Drug Designation (ODD) by US-FDA and from the European Medicine Agency. The Clinical trial is expected to start in Q2 2021.

Rigenerand is headquartered in Medolla, Modena, Italy, with more than 1,200 square metres of offices, R&D and quality control laboratories and a cell factory of 450 square metres of sterile cleanroom (EuGMP Grade-B) with BSL2/BSL3 suites for cell and gene therapies manufacturing. It combines leaders and academics from biopharma and medical device manufacturing sectors.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

Original post:
Bone Therapeutics and Rigenerand sign partnership for cell therapy process development - GlobeNewswire

Bone Marrow Stem Cells Comments Off on Bone Therapeutics and Rigenerand sign partnership for cell therapy process development – GlobeNewswire | January 14th, 2021

LONDON, Jan. 14, 2021 (GLOBE NEWSWIRE) -- New year, new updates! Our reports have been revised for market size, forecasts, and strategies to take on 2021 after the COVID-19 impact: https://www.thebusinessresearchcompany.com/global-market-reports

As per The Business Research Companys research on the global granulocyte colony stimulating factors market, the focus areas for many companies in the G-CSF market has shifted to increasing mergers and acquisitions to acquire more production capabilities. Large prime manufactures are forming joint ventures or buying small or midsized companies to acquire new capabilities or gain access to new markets.

For instance, in June 2019, Pfizer Inc., a US-based pharmaceutical corporation, acquired Array BioPharma Inc. for $48 per share in cash, for a total enterprise value of approximately $11.4 billion. This acquisition strengthens Pfizers innovative biopharmaceutical business and is expected to accelerate its growth trajectory, particularly in the long term. Array BioPharma, a US-based company, is focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer.

The G-CSF (Granulocyte Colony Stimulating Factors) market consists of sales of G-CSF drugs and related services. G-CSF-based drugs stimulate the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils through signal transduction pathways.

Granulocyte colony-stimulating factor based drugs are used to treat several pathophysiological conditions such as neutropenia (febrile neutropenia), acute radiation syndrome, auto-immune diseases and used during stem cell transplantation.

Request For A Sample Of The G-CSF (Granulocyte Colony Stimulating Factors) Market Global Report:

https://www.thebusinessresearchcompany.com/sample.aspx?id=3466&type=smp

The Business Research Companys report titled G-CSF (Granulocyte Colony Stimulating Factors) Global Market Report 2020-30: COVID-19 Growth And Change covers major G-CSF companies, Granulocyte Colony Stimulating Factorsmarket share by company, G-CSF manufacturers, G-CSF market size, and Granulocyte Colony Stimulating Factors market forecasts.

The G-CSF market is concentrated, with a small number of large players dominating the market. The top eight competitors in the market made up to 89.1% of the total market. The market is highly competitive. Companies in the market face completion for new product developments and technological advances. Major players in the market includes, Amgen Inc., Coherus Biosciences Inc., Sandoz (Novartis), Biocon/Mylan, Teva Pharmaceutcals Inc., Chugai Pharma Inc., Intalfarmaco Group, and Pfizer.

Companies in the Granolocyte Colony Stimulating Factors market are increasing their product innovation through strategic collaborations. To sustain in the increasingly competitive market, companies are developing innovative products as well as sharing skills and expertise with other companies. While companies have long collaborated with each other as well as with academic and research institutions in this market by way of partnerships, in or out-licensing deals, this trend has been increasing over recent years.

For instance, in September 2020, Humanigen, a clinical stage biopharmaceutical company collaborated with Lonza and Catalent to expand manufacturing of COVID-19 therapeutic candidate Lenzilumab. Lenzilumab is the patented Humaneered anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody with the potential to prevent and treat cytokine storm, which is believed to cause the acute respiratory distress syndrome in severe COVID-19 cases.

G-CSF (Granulocyte Colony Stimulating Factors) Market Global Report 2020-30: COVID-19 Growth And Change is one of a series of new reports from The Business Research Company that provide G-CSF market overviews, analyze and forecast Granulocyte Colony Stimulating Factors market size and growth for the whole market, G-CSF market segments and G-CSF market geographies, trends, market drivers, market restraints, G-CSF (Granulocyte Colony Stimulating Factors) market leading competitors revenues, profiles and market shares in over 1,000 industry reports, covering over 2,500 market segments and 60 geographies. The report also gives in-depth analysis of the impact of COVID-19 on the market.

The reports draw on 150,000 datasets, extensive secondary research, and exclusive insights from interviews with industry leaders. A highly experienced and expert team of analysts and modelers provides market analysis and forecasts. The reports identify top countries and segments for opportunities and strategies based on market trends and leading competitors approaches.

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Companies In The Global G-CSF (Granulocyte Colony Stimulating Factors) Market Are Focusing On Mergers And Acquisitions And Strategic Partnerships To...

Bone Marrow Stem Cells Comments Off on Companies In The Global G-CSF (Granulocyte Colony Stimulating Factors) Market Are Focusing On Mergers And Acquisitions And Strategic Partnerships To… | January 14th, 2021

-- MGTA-145: Three Phase 2 clinical trials ongoing or planned to evaluate MGTA-145, a biologic used in combination with plerixafor to mobilize stem cells; the first clinical trial in patients with multiple myeloma (initial data expected in mid-2021); the first clinical trial with matched donors and patients with acute myeloid leukemia (AML), acute lymphocytic lymphoma (ALL) and myelodysplastic syndromes (MDS) (data expected in the second half of 2021); and the first clinical trial in patients with sickle cell disease (trial initiation expected in the second half of 2021)

-- MGTA-117: Completing GLP toxicology and GMP manufacturing of targeted conditioning antibody-drug conjugate, MGTA-117; plans to initiate clinical trial in acute myeloid leukemia and myelodysplastic syndromes in mid-2021

-- Five abstracts from across Magentas pipeline, including four oral presentations, will be presented at the Transplantation and Cellular Therapy (TCT) Annual Meeting, to be held virtually February 8-12, 2021

-- Magenta also has announced the appointment of experienced biotech executive Alison Lawton to its Board of Directors --

-- Ended 2020 with cash reserves of approximately $145 million that are expected to fund the current operating plan into 2023 --

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of immune and blood systems reset via stem cell transplant to more patients, today highlighted progress across its stem cell mobilization and collection and targeted conditioning programs, and set expectations for 2021. These updates will be discussed during a webcast presentation at the 39th Annual J.P. Morgan Healthcare Conference on Thursday, January 14 at 7:50 a.m. PST / 10:50 a.m. EST.

Im exceptionally proud of the entire Magenta team who continued to adapt and execute across our portfolio, despite the disruptions that characterized 2020. This past year, we continued to drive our vision to bring immune and blood systems reset to more patients. We announced four pipeline-expanding partnerships, presented clinical and pre-clinical data across our pipeline and secured the capital that we expect can fund our operations into 2023. We continue to advance four ongoing and planned clinical trials that we believe can advance our portfolio in 2021 and, for MGTA-145 specifically, can provide proof-of-concept for stem cell mobilization across multiple diseases and the first clinical data for MGTA-117 targeted conditioning, said Jason Gardner, D. Phil., President and Chief Executive Officer, Magenta. I am also delighted to welcome Alison Lawtons return to Magentas Board of Directors. Alison brings extensive experience and leadership in both regulatory and business arenas, essential as the Magenta portfolio advances. We look forward to building on the momentum generated in 2020 as we relentlessly focus on execution.

Stem Cell Mobilization and Collection

MGTA-145: Three Phase 2 Clinical Trials Ongoing or Planned

Autologous Stem Cell Transplant of Multiple Myeloma Patients. Previously announced ongoing enrollment continues for the Phase 2 investigator-initiated clinical trial of MGTA-145, used in combination with plerixafor, to mobilize and collect stem cells for autologous stem cell transplantation in multiple myeloma patients at Stanford University. Magenta expects that this trial will provide data on stem cell mobilization and collection, durability of engraftment in transplanted patients and disease outcomes, including progression-free survival. Initial data from the study are expected in mid-2021.

Allogeneic Donor Stem Cell Mobilization and Collection for Stem Cell Transplant in AML, ALL and MDS Patients. Through a collaboration with the National Marrow Donor Program/Be The Match, Magenta plans to initiate, within the next several weeks, a Phase 2 clinical trial using MGTA-145 to mobilize and collect stem cells from allogeneic donors for transplant in patients with AML, ALL and MDS. This clinical trial will evaluate stem cell mobilization, collection, cell quality, engraftment and disease outcomes, including Graft-versus-Host Disease (GvHD), which is of particular importance in the allogeneic transplant setting. Initial data from this clinical trial are expected in the second half of 2021.

Sickle Cell Disease Stem Cell Mobilization and Collection; Cell Characterization; Pre-Clinical Gene Modification Model. In collaboration with bluebird bio, Magenta plans to initiate a Phase 2 clinical trial in the second half of 2021 to evaluate MGTA-145, in combination with plerixafor, for the mobilization and collection of stem cells in adults and adolescents with sickle cell disease (SCD). Each party will characterize the cells and Magenta plans to gene-correct the cells and transplant them into established pre-clinical disease models to evaluate engraftment. Data from this clinical trial could provide proof-of-concept for MGTA-145, in combination with plerixafor, as the preferred mobilization regimen for patients with SCD and, more broadly, across all gene therapy applications where safe, reliable and rapid mobilization of quality stem cells for gene-modification and transplant are necessary components.

About MGTA-145

Magenta is developing MGTA-145 in combination with plerixafor to harness complementary mechanisms to mobilize hematopoietic stem cells (HSCs) for collection and transplantation. This combination has the potential to be the preferred mobilization regimen for safe, rapid and reliable mobilization and collection of HSCs and could improve outcomes in autologous and allogeneic stem cell transplantation.

Targeted Conditioning

MGTA-117: Plans to Initiate Phase 1 Clinical Trial in mid-2021; Initial Safety and Pharmacokinetics (PK) data to be assessed in the fourth quarter of 2021

AML and MDS. Magenta is completing its IND-enabling GLP toxicology studies and GMP manufacturing process for MGTA-117, the first antibody-drug conjugate (ADC) candidate from the companys research platform for targeted conditioning of patients prior to receiving a stem cell transplant for blood cancers or gene therapy drug products. Later this month, Magenta expects to complete its initial discussions with the U.S. Food and Drug Administration regarding the design of the first-in-human clinical trial. Magenta expects to file an Investigational New Drug (IND) application and, upon approval, plans to initiate a Phase 1 clinical trial in mid-2021 to assess the safety and PK in the first cohort of patients in the fourth quarter of 2021.

About MGTA-117

MGTA-117, Magentas most advanced conditioning program, is a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, a payload in-licensed from Heidelberg Pharma. MGTA-117 is designed to precisely deplete only hematopoietic stem and progenitor cells to clear space in the bone marrow prior to transplant, which supports long-term engraftment and disease outcomes in patients. MGTA-117 has shown high selectivity, potent efficacy, wide safety margins and broad tolerability in non-human primate models.

Cash Guidance

With focused allocation of resources on the Companys clinical trials and advancement of its research platform, the Company now believes its cash position will fund its operations into the first quarter of 2023.

Alison Lawton Background

Ms. Lawton is an executive leader with more than 30 years of experience in biopharma. She served as President and Chief Executive Officer of Kaleido Biosciences, Inc. (Nasdaq: KLDO) from August 2018 to June 2020, and served as President and Chief Operating Officer from December 2017 to August 2018. Prior to joining Kaleido Biosciences, Inc., Ms. Lawton served as Chief Operating Officer at Aura Biosciences, Inc., an oncology therapeutics company, from January 2015 until December 2017, and, prior to joining Aura, served as a consultant to Aura from March 2014 to December 2014. From January 2013 to January 2014, Ms. Lawton served as Chief Operating Officer at OvaScience Inc., a life sciences company. From 2014 to 2017, Ms. Lawton served as a biotech consultant for various companies, including as Chief Operating Officer consultant at X4 Pharmaceuticals. Prior to that, Ms. Lawton spent more than 20 years in various positions of increasing responsibility including Senior VP and General Manager of Biosurgery and prior, Senior VP of Market Access at Genzyme Corporation, a global biopharmaceutical company, and subsequently at Sanofi S.A., also a global biopharmaceutical company, following the acquisition of Genzyme by Sanofi in 2011. Additionally, Ms. Lawton previously served two terms as the industry representative on the U.S. Food & Drug Administrations Cell & Gene Therapy Advisory Committee and as Chairman of the Board of the Regulatory Affairs Professional Society. Ms. Lawton currently serves on the boards of directors of ProQR Therapeutics N.V., X4 Pharmaceuticals Inc. and Aeglea Biotherapeutics Inc. Ms. Lawton previously served on the boards of directors of Magenta Therapeutics, Kaleido Biosciences Inc., Verastem, Inc., CoLucid Pharmaceuticals, Inc. prior to its acquisition by Eli Lilly and Cubist Pharmaceuticals, Inc. prior to its acquisition by Merck & Co. Ms. Lawton holds a B.Sc. in pharmacology from Kings College, University of London.

Upcoming Presentations at the 2021 Transplantation and Cellular Therapy (TCT) Annual Meeting

Title: MGTA-145 / Plerixafor-Mediated HSC Mobilization and Intravenous HDAd5/35++ Vector Injection into Mice Allows for Efficient In Vivo HSC Transduction and Stable Gene Marking in Peripheral Blood Cells (Oral Abstract, #16)Presenting Author: Chang Li, Ph.D., Division of Medical Genetics, Department of Medicine, University of WashingtonDate and Time of Oral Presentation: Monday, February 8, 2021, 2:30 PM CST

Title: MGTA-145, In Combination with Plerixafor in a Phase 1 Clinical Study, Mobilizes Large Numbers of Hematopoietic Stem Cells and a Graft with Potent Immunosuppressive Properties for Autologous and Allogeneic Transplant (Oral Abstract, #35)Presenting Author: Kevin Goncalves, Ph.D., Magenta TherapeuticsDate and Time of Oral Presentation: Tuesday, February 9, 2021, 3:00 PM CST

Title: MGTA-456, A CD34 Expanded Cord Blood Product, Permits Selection of Better HLA Matched Units and Results in Rapid Hematopoietic Recovery, Uniform Engraftment and Reduced Graft-Versus-Host Disease in Adults with High-Risk Hematologic Malignancies (Oral Abstract, #31)Presenting Author: Heather Stefanski, M.D., Ph.D., Assistant Professor, Department of Pediatrics, University of MinnesotaDate and Time of Oral Presentation: Tuesday, February 9, 2021, 3:00 PM CST

Title: A Single Dose of a Novel Anti-Human CD117-Amanitin Antibody Drug Conjugate (ADC) Engineered for a Short Half-life Provides Dual Conditioning and Anti-Leukemia Activity and Extends Survival Compared to Standard of Care in Multiple Pre-clinical Models of Acute Myeloid Leukemia (AML) (Oral Abstract, #53)Presenting Author: Leanne Lanieri, M.S., Magenta TherapeuticsDate and Time of Oral Presentation: Wednesday, February 10, 2021, 3:00 PM CST

Title: Targeted CD45 Antibody Drug Conjugate Enables Full Mismatch Allogeneic Hematopoietic Stem Cell Transplantation in a Murine HSCT Model as a Single Agent (AML) (Poster #242)Lead Author: Sharon Hyzy, M.S., Magenta Therapeutics

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with blood cancer, genetic diseases and autoimmune diseases. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients.

Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com.

Follow Magenta on Twitter: @magentatx.

Forward-Looking Statement

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including express or implied statements regarding Magentas future expectations, plans and prospects, including, without limitation, statements regarding expectations and plans for presenting clinical data, projections regarding our long-term growth, cash, cash equivalents and marketable securities, the anticipated timing of our clinical trials and regulatory filings, the development of our product candidates and advancement of our clinical programs, the timing, progress and success of our collaborations, as well as other statements containing words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions that can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial will be predictive of the final results of the trial; whether results from pre-clinical studies or earlier clinical studies will be predictive of the results of future trials; the expected timing of submissions for regulatory approval or review by governmental authorities; regulatory approvals to conduct trials or to market products; whether Magenta's cash resources will be sufficient to fund Magenta's foreseeable and unforeseeable operating expenses and capital expenditure requirements; risks, assumptions and uncertainties regarding the impact of the continuing COVID-19 pandemic on Magentas business, operations, strategy, goals and anticipated timelines, Magentas ongoing and planned pre-clinical activities, Magentas ability to initiate, enroll, conduct or complete ongoing and planned clinical trials, Magentas timelines for regulatory submissions and Magentas financial position; and other risks concerning Magenta's programs and operations set forth under the caption Risk Factors in Magentas Annual Report on Form 10-K filed on March 3, 2020, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Magenta Therapeutics:Lyndsey Scull, Director, Corporate Communications, Magenta Therapeutics202-213-7086lscull@magentatx.com

Investor inquiries:Jill Bertotti, W2O Group714-225-6726jbertotti@w2ogroup.com

Media inquiries:Dan Budwick1ABdan@1abmedia.com

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Magenta Therapeutics Highlights Recent Progress and Expected Timing of 2021 Milestones, Including Fo - PharmiWeb.com

Bone Marrow Stem Cells Comments Off on Magenta Therapeutics Highlights Recent Progress and Expected Timing of 2021 Milestones, Including Fo – PharmiWeb.com | January 14th, 2021

SACRAMENTO, Calif., Jan. 12, 2021 /PRNewswire/ --The Sacramento Metropolitan Chamber of Commerce announced it will name Cate Dyer, CEO of StemExpress, the "Businesswoman of the Year" at their 126th Annual Business Awards. Since 1895, Metro Chamber has recognized Sacramento's most esteemed players in the business community. The 2021 Annual Dinner and Business Awards will be held virtually for the first time, and Ms. Dyer will receive this extraordinary honor on February 5th, 2021.

Ms. Dyer founded StemExpress in 2010 to accelerate the cure and prevention of significant medical conditions at life-changing speed. StemExpress supports medical research, clinical trials, commercialization of disease specific treatment, cell and gene therapies, precision and regenerative medicine, as well as researchers and clinicians from all around the world who are developing new treatments and cures. StemExpress has a network of healthcare partnerships that includes over 50 hospitals in Europe as well as three (3) US healthcare systems that encompasses 31 hospitals, 35 outpatient facilities and 20 individual practices. StemExpress is currently the nation's leading biospecimen provider of human primary cells, stem cells, human bone marrow, cord blood, peripheral blood, maternal blood, and disease-state products for academic, biotechnological, diagnostic, pharmaceutical and contract research organizations. StemExpress is registered with the U.S. Food and Drug Administration (FDA) and has seven (7) independently owned and operated brick-and mortar cellular clinics across the United States to collect blood, cells and tissue from patients and donors. These clinics include state-of-the-art cell manufacturing laboratories for clinical and research purposes, and CLIA certified/high-complexity diagnostics.

Since inception, StemExpress has been committed to transformative, positive impacts on the community. In line with this commitment, StemExpress immediately recognized the unparalleled challenges the COVID-19 virus presented to its communities, healthcare entities, local businesses, and the economy at large. In a matter of weeks, the company built out a seamless, end-to-end COVID-19 testing solution, all while continuing to grow its core cellular business. This end-to-end solution includes on-line patient registration, scheduling, specimen collection, pop-up site management, and laboratory testing using gold-standard PCR testing at high-volume capacity with rapid turn-around times. StemExpress directly and proudly supports frontline workers, inner city communities, hospitals, skilled nursing facilities, school districts, correctional facilities, utility companies, major league sports, tribal territories and territorial governments, among others. Through public health partnerships, StemExpress has also provided free testing services to vulnerable members of the community, including the uninsured and other under-represented populations.

The 2021 Annual Business Awards will pay tribute to Cate Dyer's extraordinary effort to support Sacramento's communities, businesses, and the heroes who keep our economy moving.

Contact: [emailprotected]

SOURCE StemExpress

https://www.stemexpress.com

Continued here:
Cate Dyer of StemExpress is Named Businesswoman of the Year! - PRNewswire

Bone Marrow Stem Cells Comments Off on Cate Dyer of StemExpress is Named Businesswoman of the Year! – PRNewswire | January 14th, 2021

TAMPA, Fla.--(BUSINESS WIRE)--The technology, developed by scientists at Memorial Sloan Kettering Cancer Center ("MSKCC"), headed by Dr. Michel Sadelain and Errant Gene Therapeutics, is a one-time treatment that inserts an encoded gene into a patient's own bone marrow stem cells restoring the production of normal hemoglobin. This technology is known as Thalagen.

In June of 2020, an abstract was released to the European Hematology Association (EHA) noting the results of patients treated in a clinical trial at MSK with the EGT vector. The abstract is based on patients treated with the 2009 EGT-produced vector in the MSK Clinical Trial. The EHA abstract, submitted by Simona Raso, reports that 2 out of 3 Thalassemia patients treated with EGTs vector have sustained dramatic reduction in blood transfusions after 8 and 5 years, respectively. These 3 patients are the only Thalassemic patients treated with Lentiglobin in the US for whom there is an 8-year follow-up. The abstract is publicly available on the European Hematology Associations website at the following address:

https://library.ehaweb.org/eha/2020/eha25th/293982/simona.raso.gene.therapy.with.the.lentiviral.vector.tns9.3.55.produces.html?f=menu%3D14%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Aspeaker%3D731017.

The reductions in transfusions for the patients reported in the EHA abstract means a marked reduction in risk and damage created by the chronic transfusions, transferred diseases and iron build-up. One of the patients with significant transfusion deduction used the EGT-produced vector with a mild chemotherapeutic prep-regimen. The abstract does not report any clonal dominance. EGT is the only company with experience in development of a non-myeloablative potential treatment for Thalassemia patients.

EGT produced the worlds first commercial batch of gene therapy vector in 2009. The EGT vector uses the wild-type beta globin gene, the most natural form of the gene.

EGT Founder, Patrick Girondi noted, After some delay, we are happy to be moving forward once again, and the EHA abstract is incredible news for patients. Today, with modern production, enhancers, improved filtration and other prep regimen drugs, we believe that the vector EGT will produce in 2021, honed by 12 years of advancement in the field and using modern transduction enhancers will cure Thalassemia patients and that EGT will make quick headway towards curing Sickle Cell patients using the same therapy.

EGT, a gene therapy pioneers goal is to make medicines which are safe and accessible to patients. EGT believes the EGT vector to be more natural and therefore safer. Additionally, the cost of the treatment is drastically lower than that of competing products. EGT will work with regulatory agencies to continue the trial, formerly sponsored by Memorial Sloan Kettering Cancer Center NCT01639690.

Ronald Capano of Cooleys Anemia International says, This clinical trial means so much to so many and represents the work and dedication of our organization and that of the family and friends of all Thalassemia and Sickle Cell anemia patients, particularly those with compromised organs.

About Errant Gene Therapeutics, LLC

Errant Gene Therapeutics (also known as EGT) is a privately held biopharmaceutical company established in 2003 headquartered in Tampa, Florida. In addition to its ongoing support of gene therapy for beta-thalassemia and Sickle Cell anemia, EGT is a pioneer in the emerging field of epigenetics, and its patented portfolio of small molecule histone deacetylase inhibitors, which change the way cells express their genetic material. EGTs lead compound, CG-1521, targets inflammatory breast cancer and hormone refractory prostate cancer. CG-1521 results have been published in scientific venues.

Excerpt from:
Errant Gene Therapeutics, LLC (EGT) Pushing Clinical Trial of Potentially Curative Treatment for Beta-Thalassemia and Eventually Sickle Cell Disease -...

Bone Marrow Stem Cells Comments Off on Errant Gene Therapeutics, LLC (EGT) Pushing Clinical Trial of Potentially Curative Treatment for Beta-Thalassemia and Eventually Sickle Cell Disease -… | January 14th, 2021

The technology, developed by scientists at Memorial Sloan Kettering Cancer Center ("MSKCC"), headed by Dr. Michel Sadelain and Errant Gene Therapeutics, is a one-time treatment that inserts an encoded gene into a patient's own bone marrow stem cells restoring the production of normal hemoglobin. This technology is known as Thalagen.

In June of 2020, an abstract was released to the European Hematology Association (EHA) noting the results of patients treated in a clinical trial at MSK with the EGT vector. The abstract is based on patients treated with the 2009 EGT-produced vector in the MSK Clinical Trial. The EHA abstract, submitted by Simona Raso, reports that 2 out of 3 Thalassemia patients treated with EGTs vector have sustained dramatic reduction in blood transfusions after 8 and 5 years, respectively. These 3 patients are the only Thalassemic patients treated with Lentiglobin in the US for whom there is an 8-year follow-up. The abstract is publicly available on the European Hematology Associations website at the following address:

https://library.ehaweb.org/eha/2020/eha25th/293982/simona.raso.gene.therapy.with.the.lentiviral.vector.tns9.3.55.produces.html?f=menu%3D14%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Aspeaker%3D731017.

The reductions in transfusions for the patients reported in the EHA abstract means a marked reduction in risk and damage created by the chronic transfusions, transferred diseases and iron build-up. One of the patients with significant transfusion deduction used the EGT-produced vector with a mild chemotherapeutic prep-regimen. The abstract does not report any clonal dominance. EGT is the only company with experience in development of a non-myeloablative potential treatment for Thalassemia patients.

EGT produced the worlds first commercial batch of gene therapy vector in 2009. The EGT vector uses the wild-type beta globin gene, the most natural form of the gene.

EGT Founder, Patrick Girondi noted, "After some delay, we are happy to be moving forward once again, and the EHA abstract is incredible news for patients. Today, with modern production, enhancers, improved filtration and other prep regimen drugs, we believe that the vector EGT will produce in 2021, honed by 12 years of advancement in the field and using modern transduction enhancers will cure Thalassemia patients and that EGT will make quick headway towards curing Sickle Cell patients using the same therapy."

Story continues

EGT, a gene therapy pioneers goal is to make medicines which are safe and accessible to patients. EGT believes the EGT vector to be more natural and therefore safer. Additionally, the cost of the treatment is drastically lower than that of competing products. EGT will work with regulatory agencies to continue the trial, formerly sponsored by Memorial Sloan Kettering Cancer Center NCT01639690.

Ronald Capano of Cooleys Anemia International says, "This clinical trial means so much to so many and represents the work and dedication of our organization and that of the family and friends of all Thalassemia and Sickle Cell anemia patients, particularly those with compromised organs."

About Errant Gene Therapeutics, LLC

Errant Gene Therapeutics (also known as EGT) is a privately held biopharmaceutical company established in 2003 headquartered in Tampa, Florida. In addition to its ongoing support of gene therapy for beta-thalassemia and Sickle Cell anemia, EGT is a pioneer in the emerging field of epigenetics, and its patented portfolio of small molecule histone deacetylase inhibitors, which change the way cells express their genetic material. EGTs lead compound, CG-1521, targets inflammatory breast cancer and hormone refractory prostate cancer. CG-1521 results have been published in scientific venues.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210111005273/en/

Contacts

Patrick Girondi, Founderpgirondi@errantgene.com (312) 441-1800 Office(312) 498-0025 Cell

Jason Feldman, BDOjfeldman@errantgene.com (312) 441-1800 x11

Here is the original post:
Errant Gene Therapeutics, LLC ("EGT") Pushing Clinical Trial of Potentially Curative Treatment for Beta-Thalassemia and Eventually Sickle...

Bone Marrow Stem Cells Comments Off on Errant Gene Therapeutics, LLC ("EGT") Pushing Clinical Trial of Potentially Curative Treatment for Beta-Thalassemia and Eventually Sickle… | January 14th, 2021

Public Health England (PHE) created this information on behalf of the NHS. In this information, the word we refers to the NHS service that provides screening.

You should read this information if the result of your antenatal screening test for sickle cell and thalassaemia (SCT) shows you are at risk of having a baby with sickle cell disease.

This is because your blood test showed that:

This information will help you and your health professional talk through the next stages of your care during this pregnancy. It should support, but not replace, any discussions you have.

This information explains:

Sickle cell disease is the name for a group of conditions inherited from biological parents that affect the haemoglobin in red blood cells. The most serious type is called sickle cell anaemia.

In the UK, sickle cell disease is most common in people with an African or Caribbean family background, but it is also seen in people with family origins from other parts of the world.

People with sickle cell disease have red blood cells that can become misshapen, which:

Sickle cell disease is a serious lifelong condition, but long-term treatment can help manage many of the symptoms. People with sickle cell disease can lead long, active and fulfilling lives if they manage their condition well and have the right care and support.

The main symptoms of sickle cell disease are:

Other symptoms can include delayed growth, strokes and lung problems.

People with sickle cell disease need specialist care throughout their lives. Daily antibiotics and regular vaccinations can reduce the risk of infections. Blood transfusions can also be given to treat serious cases of anaemia. Some children with sickle cell disease benefit from taking a medicine called hydroxycarbamide which helps prevent many complications.

People with sickle cell disease can do a number of things to manage pain, avoid infections and stay as healthy as possible. Your healthcare professional can give you more advice about living with sickle cell disease.

The only cure for sickle cell disease is a bone marrow (or stem cell) transplant, which replaces damaged blood cells with healthy ones. This is a complicated procedure which is only suitable for people with serious complications from the disease who have a matching donor.

Sickle cell disease is inherited from genes passed on by both biological parents. It is not a result of anything you have or have not done.

If both biological parents are carriers of the haemoglobin gene, known as haemoglobin S, their baby can inherit the haemoglobin S gene from both of them. This is the most common and most serious type of sickle cell disease.

Babies can inherit other types of sickle cell disease if one parent carries the sickle cell gene (haemoglobin S) and the other parent has another haemoglobin gene such as beta thalassaemia or haemoglobin C. Your health professional can discuss this with you, so that you understand exactly what condition your baby could inherit, and how serious it could be.

If you and your childs biological father are both carriers then there is a 1 in 4 (25%) chance your child will inherit sickle cell disease. There is a 2 in 4 (50%) chance that your child will be a carrier, and a 1 in 4 (25%) chance your child will have normal haemoglobin. These chances are the same in every pregnancy when both parents are carriers.

The diagram below shows how genetic inheritance works. Both parents in this diagram are carriers. They are drawn in 2 colours to show they have one usual haemoglobin gene (green) and one unusual gene (blue).

There is a 1 in 4 chance of this baby inheriting the condition, a 2 in 4 chance of them being a carrier and a 1 in 4 chance they will not have the condition.

You can choose if you want a test to find out for sure if your unborn baby has inherited sickle cell disease or not. This is called prenatal diagnosis (PND). It is your decision to have this test or not.

All babies are offered the newborn blood spot test for sickle cell disease whether a PND has been carried out or not. The test is offered when the baby is 5 days old and results received before the baby is 28 days old.

You will be offered either a chorionic villus sampling (CVS) or amniocentesis diagnostic test.

CVS tests are usually done between 11 and 14 weeks of pregnancy but can be done later.

Amniocentesis tests are usually done between 15 and 20 weeks of pregnancy.

There are 3 possible results from a PND test. It can show that your baby:

In rare cases the screening laboratory cannot give a result. If this happens, you will be contacted and offered a repeat PND test.

If the result shows that your baby has normal haemoglobin or is a carrier, then your pregnancy care will continue as usual.

If a PND test shows your baby has inherited sickle cell disease, your healthcare professional will talk to you and offer support. You should also have the chance to talk to a specialist.

You may choose to:

If you decide to continue with the pregnancy the specialist team will:

If you decide to end your pregnancy the specialist team will give you information about what this involves and how you will be supported.

Only you know what is the best decision for your family.

Whatever decision you make, your healthcare professionals will support you.

If you and your partner are planning a pregnancy and are both carriers, there is a 1 in 4 (25%) chance your baby could inherit sickle cell disease. These chances are the same in each and every pregnancy that you have together.

You may discuss the following with your GP, midwife or specialist counsellor:

This can be performed after 11 weeks giving more time to consider your choices if the baby has sickle cell disease. You would need to see your GP or midwife as soon as you know you are pregnant.

PGD is a reproductive treatment used in in-vitro fertilisation (IVF) which involves checking the genes or chromosomes of your embryos for a specific genetic condition. It can help to avoid a pregnancy with a genetic condition for which a couple is at risk. You can ask to see a genetic counsellor to discuss this option.

This means either you or your partner would not be a biological parent of your baby. You can discuss this option with your healthcare professional.

For more information, see:

The NHS Screening Programmes use personal information from your NHS records to invite you for screening at the right time. Public Health England also uses your information to ensure you receive high quality care and to improve the screening programmes. Find out more about how your information is used and protected, and your options.

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Information and choices for women and couples at risk of having a baby with sickle cell disease - GOV.UK

Bone Marrow Stem Cells Comments Off on Information and choices for women and couples at risk of having a baby with sickle cell disease – GOV.UK | January 14th, 2021

DGAP-News: MorphoSys AG / Key word(s): Miscellaneous12.01.2021 / 22:00 The issuer is solely responsible for the content of this announcement.

Media Release

MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab

PLANEGG/MUNICH, Germany and MONTREAL, Canada - January 12, 2021 - MorphoSys AG (FSE: MOR; Prime Standard Segment; MDAX & TecDAX; NASDAQ:MOR) and Incyte (NASDAQ: INCY) today announced that Health Canada has accepted the New Drug Submission (NDS) for tafasitamab, an anti-CD19 antibody. The application seeks approval of tafasitamab in combination with lenalidomide, followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma, who are not eligible for, or refuse, autologous stem cell transplant (ASCT).

"With the acceptance of the NDS by Health Canada, review of the data can begin, an important step on the path to making tafasitamab available in Canada for use in combination with lenalidomide in eligible patients with relapsed or refractory DLBCL," said Jose Brisebois, Ph.D., Head of Medical Affairs, Incyte Biosciences Canada. "We intend to work closely with Health Canada as we seek to bring this innovative targeted therapeutic option to the clinical community and to appropriate patients for whom few treatment options exist."

"This important milestone moves tafasitamab in combination with lenalidomide into the regulatory review process in Canada, with the potential to significantly advance patient care in the treatment of relapsed or refractory DLBCL," said Nuwan Kurukulasuriya, Ph.D., Senior Vice President Global Medical Affairs, MorphoSys.

The NDS, submitted by Incyte, is based on data from the L-MIND study evaluating tafasitamab in combination with lenalidomide as a treatment for patients with relapsed or refractory DLBCL not eligible for autologous stem cell transplant, and is supported by the RE-MIND study, an observational retrospective study in relapsed or refractory DLBCL.

Incyte has exclusive commercialization rights for tafasitamab outside of the United States and, if approved, Incyte will hold the marketing authorization for tafasitamab in Canada. This NDS marks the second marketing application that Incyte Biosciences Canada has made to Health Canada since establishing operations in Canada in April 2020.

About Diffuse Large B-cell Lymphoma (DLBCL)DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide1, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about 40% of patients not responding to initial therapy or relapsing thereafter2, leading to a high medical need for new, effective therapies3, especially for patients who are not eligible for an autologous stem cell transplant in this setting.

About L-MINDThe L-MIND trial is a single arm, open-label, multicenter Phase 2 study (NCT02399085) investigating the combination of tafasitamab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have had at least one, but no more than three prior lines of therapy, including an anti-CD20 targeting therapy (e.g. rituximab), who are not eligible for high-dose chemotherapy or refuse subsequent autologous stem cell transplant. The study's primary endpoint is Overall Response Rate (ORR). Secondary outcome measures include Duration of Response (DoR), Progression-Free Survival (PFS) and Overall Survival (OS). In May 2019, the study reached its primary completion.

For more information about L-MIND, visit https://clinicaltrials.gov/ct2/show/NCT02399085

About RE-MINDRE-MIND, an observational retrospective study (NCT04150328), was designed to isolate the contribution of tafasitamab in combination with lenalidomide and to prove the combinatorial effect. The study compares real-world response data of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received lenalidomide monotherapy with the efficacy outcomes of the tafasitamab-lenalidomide combination, as investigated in MorphoSys' L-MIND trial. RE-MIND collected the efficacy data from 490 relapsed or refractory DLBCL patients in the U.S. and EU. Qualification criteria for matching patients of both studies were pre-specified. As a result, 76 eligible RE-MIND patients were identified and matched 1:1 to 76 of 80 L-MIND patients based on important baseline characteristics. Objective Response Rates (ORR) were validated based on this subset of 76 patients in RE-MIND and L-MIND, respectively. The primary endpoint of RE-MIND was met and shows a statistically significant superior best ORR of the tafasitamab-lenalidomide combination compared to lenalidomide monotherapy.

For more information about RE-MIND, visit https://clinicaltrials.gov/ct2/show/NCT04150328.

About TafasitamabTafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb(R) engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP). In January 2020, MorphoSys and Incyte entered into a collaboration and licensing agreement to further develop and commercialize tafasitamab globally. Following approval by the U.S. Food and Drug Administration in July 2020, tafasitamab is being co-commercialized by MorphoSys and Incyte in the United States. Incyte has exclusive commercialization rights outside the United States.

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in a number of ongoing combination trials.

XmAb(R) is a registered trademark of Xencor, Inc.

The safety and efficacy of tafasitamab is under review and the market authorization in Canada has not yet been obtained.

About MorphoSysMorphoSys (FSE & NASDAQ: MOR) is a commercial-stage biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapies for patients suffering from cancer and autoimmune diseases. Based on its leading expertise in antibody, protein and peptide technologies, MorphoSys, together with its partners, has developed and contributed to the development of more than 100 product candidates, of which 27 are currently in clinical development. In 2017, Tremfya(R), developed by Janssen Research & Development, LLC and marketed by Janssen Biotech, Inc., for the treatment of plaque psoriasis, became the first drug based on MorphoSys' antibody technology to receive regulatory approval. In July 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval of MorphoSys' proprietary product Monjuvi(R) (tafasitamab-cxix) in combination with lenalidomide in patients with a certain type of lymphoma. Headquartered near Munich, Germany, the MorphoSys group, including the fully owned U.S. subsidiary MorphoSys US Inc., has more than 600 employees. More information at http://www.morphosys.com or http://www.morphosys-us.com.

Monjuvi(R) is a registered trademark of MorphoSys AG.

Tremfya(R) is a registered trademark of Janssen Biotech, Inc.

About Incyte Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

MorphoSys Forward-looking Statements This communication contains certain forward-looking statements concerning the MorphoSys group of companies, including the expectations regarding Monjuvi's ability to treat patients with relapsed or refractory diffuse large B-cell lymphoma, the further clinical development of tafasitamab-cxix, including ongoing confirmatory trials, additional interactions with regulatory authorities and expectations regarding future regulatory filings and possible additional approvals for tafasitamab-cxix as well as the commercial performance of Monjuvi. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "would," "could," "potential," "possible," "hope" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve known and unknown risks and uncertainties, which might cause the actual results, financial condition and liquidity, performance or achievements of MorphoSys, or industry results, to be materially different from any historic or future results, financial conditions and liquidity, performance or achievements expressed or implied by such forward-looking statements. In addition, even if MorphoSys' results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. Among the factors that may result in differences are MorphoSys' expectations regarding risks and uncertainties related to the impact of the COVID-19 pandemic to MorphoSys' business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products, the global collaboration and license agreement for tafasitamab, the further clinical development of tafasitamab, including ongoing confirmatory trials, and MorphoSys' ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials, additional interactions with regulatory authorities and expectations regarding future regulatory filings and possible additional approvals for tafasitamab-cxix as well as the commercial performance of Monjuvi, MorphoSys' reliance on collaborations with third parties, estimating the commercial potential of its development programs and other risks indicated in the risk factors included in MorphoSys' Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. MorphoSys expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements, unless specifically required by law or regulation.

Incyte Forward-looking Statements Except for the historical information set forth herein, the matters set forth in this press release, including statements regarding whether or when tafasitamab might be approved in Canada for the treatment of, and whether or when tafasitamab might provide a successful treatment option for, in combination with lenalidomide, certain patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and the L-MIND and RE-MIND clinical trial programs. These forward-looking statements are based on the Company's current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials; determinations made by Canadian regulatory authorities or other regulatory authorities, including the U.S. FDA; the Company's dependence on its relationships with its collaboration partners; the efficacy or safety of the Company's products and the products of the Company's collaboration partners; the acceptance of the Company's products and the products of the Company's collaboration partners in the marketplace; market competition; sales, marketing, manufacturing and distribution requirements; greater than expected expenses; expenses relating to litigation or strategic activities; and other risks detailed from time to time in the Company's reports filed with the Securities and Exchange Commission, including its Form 10-Q for the quarter ending September 30, 2020. The Company disclaims any intent or obligation to update these forward-looking statements.

Contacts:

References1Sarkozy C, et al. Management of relapsed/refractory DLBCL. Best Practice Research & Clinical Haematology. 2018 31:209-16. doi.org/10.1016/j.beha.2018.07.014.2 Skrabek P, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Current Oncology. 2019 26(4): 253-265. doi.org/10.3747/co.26.5421.3 Skrabek P, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Current Oncology. 2019 26(4): 253-265. doi.org/10.3747/co.26.5421.

12.01.2021 Dissemination of a Corporate News, transmitted by DGAP - a service of EQS Group AG.The issuer is solely responsible for the content of this announcement.

The DGAP Distribution Services include Regulatory Announcements, Financial/Corporate News and Press Releases. Archive at http://www.dgap.de

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MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab - PharmiWeb.com

Bone Marrow Stem Cells Comments Off on MorphoSys and Incyte Announce Acceptance by Health Canada of the New Drug Submission for Tafasitamab – PharmiWeb.com | January 14th, 2021

Abowl of hot soup or warm broth can take the chill out of a cold winter day. While grocery store shelves are usually stocked with an array of canned and boxed varieties, making a delicious broth for sipping or a stock as a base for other soups and recipes is something you can do while doing other things, such as working on your computer or doing the laundry. Once you get it going, you only have to check on it occasionally until it's done.

According to Food & Wine, the difference between stock and broth is minimal. A stock is to be made with bones in addition to a mirepoix, a mix of carrots, onions and celery. At its most basic, broth is simply any liquid that meat has been cooked in. A broth can also be made with just vegetables. While broth is something you sip, stock is typically used as a base in sauces and soups, providing body rather than flavor.

As author Sally Fallon Morell points out in her book, "Nourishing Broth: An Old-Fashioned Remedy for the Modern World," bone broth has rich dissolves of collagen, cartilage, bone and marrow which give the body the right stuff to rebuild and rejuvenatestuff such as vitamins, minerals, amino acids and healing sugars.

"Deep in the center of bones is marrow, a creamy substance valued by our ancestors for its life-giving, reproduction-enhancing, and brain-building fat and cholesterol. As the seed of blood and stem cells, it's prized as a sacred, energizing, and regenerative food in native cultures all over the world," Morell writes. Of course, most are aware of the benefits of eating plenty of plants in our diet, too.

Whether you're going for bones or carrots or both, the basic technique is the same. Simmer veggie scraps or bones in water for a long, slow time (in the case of straight-up vegetable broth, it can be finished in one hour or less).

Simple Vegetable BrothA swirl of your favorite oil1 onion, chopped2 stalks celery, chopped2 large carrots, choppedLeftover vegetable scraps you have on hand (onion skins, carrot ends, celery leaves, herbs, potato peels, greens, etc.)Several cloves of garlic, smashedFresh parsley/thymePinch of saltTwo bay leavesWater to cover

Saut chopped veggies in a bit of oil or water to soften. Add salt, herbs, bay leaves and water to cover. Bring to almost boiling, then turn heat down to simmer for 45-60 minutes, longer if desired. Strain. Cool.

Basic Bone Broth

Roast bones on baking sheet in hot oven (400 degrees) for 30 minutes. Place bones and vegetables in big pot. Cover with water. Bring to an easy roll then immediately turn heat down. Simmer uncovered, skimming scum as it rises. Cook for 24-72 hours. Turn off overnight, turn back on to simmer next morning. During last 10 minutes of cooking, toss in fresh parsley for added flavor. Let broth cool before straining. Store in fridge up to one week or freezer up to six months.

Pro Tips:

The number one goal for bone broth/stock is to get it gelatinous, meaning it sets up in a solid gel if you put it in the fridge. Bones, such as knucklebones and chicken/pig feet with lots of cartilage help make the broth gelatinous. Include meaty bones, such as short ribs, to add flavor.

Water should just cover the bones.

Never overheat the broth/stock. A roiling boil will break down collagen fibers that won't coagulate when cooled. So heat over medium heat only until the liquid starts to "roll," then turn the heat down until it barely simmers.

Simmer with the lid off to prevent boiling and allow the gradual reduction of the stock and concentration of gelatin.

To avoid cloudiness, skim the scum that rises to the top as the liquid starts to cook and occasionally throughout cooking.

To freeze stock, only fill the container full.

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Warm Up with Homemade Broths and Stocks - The Source Weekly

Bone Marrow Stem Cells Comments Off on Warm Up with Homemade Broths and Stocks – The Source Weekly | January 14th, 2021

CARLSBAD, Calif., Jan. 12, 2021 /PRNewswire/ Today Callaway Golf Company (NYSE: ELY), an industry leader in golf equipment and innovation, announced its new family of Apex Irons and Apex Hybrids. These irons provide exceptional forged performance and A.I.-designed ball speed technologies for a wide range of players. And the hybrids feature new Jailbreak A.I. Velocity Blades for fast ball speeds in versatile, high performance offerings.

Apex 21, Apex Pro 21, and Apex DCB Irons

Apex is widely recognized for establishing the forged distance category, and the Apex 21 Irons deliver an exceptional level of performance and craftsmanship. They're the first forged Apex irons with an A.I-designed Flash Face Cup, for high ball speeds and increased spin robustness across the face. Increased forgiveness comes from a massive Tungsten Energy Core, while the 100% forged body and proprietary urethane microspheres deliver remarkable sound and feel at impact. Callaway has also enhanced the shaping for even better turf interaction.

In the players category, new Apex Pro 21 Irons promote Tour distance and performance for scratch or single-digit handicap golfers. They also utilize an A.I.-designed Flash Face in each iron for high COR's and fast ball speeds, along with extremely soft feel from an all-new forged 1025 hollow body construction and urethane microspheres. There are up to 90 grams of tungsten in the longer irons, the most ever for any Apex model, to improve launch characteristics while simultaneously improving forgiveness.

In the game-improvement category, new Apex DCB Irons extend the forged Apex offering to a wider group of golfers than ever before. They combine the look, feel and performance of a forged players club with the forgiveness of a deep cavity back. The deep cavity back design and enhanced sole width promote easy launch and solid turf interaction out of a variety of lies. The irons are engineered with an A.I.-designed Flash Face Cup, up to 50 grams of tungsten per iron for outstanding launch and forgiveness on off-center hits, and forged feel.

All of these Apex Irons will be available for online pre-order on January 26, and at retail on February 11, at a price of $1,480 for a standard 8-piece steel set ($185 per individual steel iron), and $1,600 for a standard 8-piece graphite set ($200 per individual graphite iron). Combo sets are also available.

Apex 21 and Apex Pro 21 Hybrids

The Apex 21 Hybrids are suited to help a wide range of players. They feature new Jailbreak A.I. Velocity Blades designed to increase vertical stiffness near the sole of the club, promoting more speed low on the face where players often mishit their hybrids. The blades allow the Face Cup to flex on the crown to create better spin rate consistency, and the bars are spread to enhance torsional stiffness, to provide more forgiveness across the face.

Every model and every face in the Apex Hybrids are uniquely designed using advanced A.I. This proven ball speed technology puts an even greater emphasis on center and off-center ball speeds. To create high launch and forgiveness. Callaway has implemented a massive amount of tungsten, and the adjustable hosel helps to optimize loft, trajectory and control.

Apex Pro Hybrids also incorporate Jailbreak A.I. Velocity Blades and an A.I-designed Flash Face. The Forged 455 steel provides strength and flexibility, while the iron-like design and fixed hosel create a look at address that highly skilled players prefer.

These new hybrids will all be available for online pre-order on January 26, and at retail on February 11, at a price of $269.99 each.

The Apex Family

Apex is synonymous with legendary performance and we've created a truly special offering with our new 2021 lineup, said Callaway Sr. VP of R&D, Dr. Alan Hocknell. Now we've implemented A.I.-designed ball speeds, enhanced launch characteristics, and reliable forgiveness to advance this iconic name. There's nothing like our best, and that's Apex.

About Callaway Golf Company Callaway Golf Company (NYSE: ELY) is a premium golf equipment and active lifestyle company with a portfolio of global brands, including Callaway Golf, Odyssey, OGIO, TravisMathew and Jack Wolfskin. Through an unwavering commitment to innovation, Callaway manufactures and sells premium golf clubs, golf balls, golf and lifestyle bags, golf and lifestyle apparel and other accessories. For more information please visitwww.callawaygolf.com, http://www.odysseygolf.com,www.ogio.com, http://www.travismathew.com,andwww.jack-wolfskin.com.

MEDIA CONTACTS: Jeff NewtonCallaway Golf Company[emailprotected]

View original content to download multimedia:http://www.prnewswire.com/news-releases/callaway-golf-announces-new-apex-irons-and-hybrids-301205740.html

SOURCE Callaway Golf

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Gamida Cell to Present Full Data from Phase 3 Study of Omidubicel at TCT, the Combined Transplantation and Cellular Therapy Meetings of ASTCT and...

Bone Marrow Stem Cells Comments Off on Gamida Cell to Present Full Data from Phase 3 Study of Omidubicel at TCT, the Combined Transplantation and Cellular Therapy Meetings of ASTCT and… | January 12th, 2021

Bone marrow aspiration and trephine biopsy are usually performed on the back of the hipbone, or posterior iliac crest. An aspirate can also be obtained from the sternum (breastbone). For the sternal aspirate, the patient lies on their back, with a pillow under the shoulder to raise the chest. A trephine biopsy should never be performed on the sternum, due to the risk of injury to blood vessels, lungs or the heart.

The need to selectively isolate and concentrate selective cells, such as mononuclear cells, allogeneic cancer cells, T cells and others, is driving the market. Over 30,000 bone marrow transplants occur every year. The explosive growth of stem cells therapies represents the largest growth opportunity for bone marrow processing systems.

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Europe and North America spearheaded the market as of 2018, by contributing over 74.0% to the overall revenue. Majority of stem cell transplants are conducted in Europe, and it is one of the major factors contributing to the lucrative share in the cell harvesting system market.

In 2018, North America dominated the research landscape as more than 54.0% of stem cell clinical trials were conducted in this region. The region also accounts for the second largest number of stem cell transplantation, which is further driving the demand for harvesting in the region.

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Asia Pacific is anticipated to witness lucrative growth over the forecast period, owing to rising incidence of chronic diseases and increasing demand for stem cell transplantation along with stem cell-based therapy. Japan and China are the biggest markets for harvesting systems in Asia Pacific. Emerging countries such as Mexico, South Korea, and South Africa are also expected to report lucrative growth over the forecast period. Growing investment by government bodies on stem cell-based research and increase in aging population can be attributed to the increasing demand for these therapies in these countries.

Major players operating in the global bone marrow processing systems market are ThermoGenesis (Cesca Therapeutics inc.), RegenMed Systems Inc., MK Alliance Inc., Fresenius Kabi AG, Harvest Technologies (Terumo BCT), Arthrex, Inc. and others.

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Bone Marrow Processing Systems Market Recent developments in the competitive landscape forecast 2018 2025 - SoccerNurds

Bone Marrow Stem Cells Comments Off on Bone Marrow Processing Systems Market Recent developments in the competitive landscape forecast 2018 2025 – SoccerNurds | January 12th, 2021