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Researchers have found a way, in mice and human tissue, to regenerate the cartilage that eases movement between bones.

Loss of this slippery and shock-absorbing tissue layer, called articular cartilage, is responsible for many cases of joint pain and arthritis, which afflicts more than 55 million Americans.

The researchers can envision a time when people are able to avoid getting arthritis in the first place by rejuvenating their cartilage before it is badly degraded.

Nearly 1 in 4 adult Americans suffer from arthritis, and far more are burdened by joint pain and inflammation generally.

The researchers figured out how to regrow articular cartilage by first causing slight injury to the joint tissue, then using chemical signals to steer the growth of skeletal stem cells as the injuries heal.

Cartilage has practically zero regenerative potential in adulthood, so once its injured or gone, what we can do for patients has been very limited, says co-senior author Charles K.F. Chan, assistant professor of surgery at Stanford Universitys School of Medicine.

Its extremely gratifying to find a way to help the body regrow this important tissue, Chan says.

The work builds on previous research that resulted in isolation of the skeletal stem cell, a self-renewing cell that is also responsible for the production of bone, cartilage and a special type of cell that helps blood cells develop in bone marrow.

Articular cartilage is a complex and specialized tissue that provides a slick and bouncy cushion between bones at the joints. When this cartilage is damaged by trauma, disease, or simply thins with age, bones can rub directly against each other, causing pain and inflammation, which can eventually result in arthritis.

Damaged cartilage can be treated through a technique called microfracture, in which tiny holes are drilled in the surface of a joint. The microfracture technique prompts the body to create new tissue in the joint, but the new tissue is not much like cartilage.

I realized the only way to understand the process was to look at what stem cells are doing after microfracture.

Microfracture results in what is called fibrocartilage, which is really more like scar tissue than natural cartilage, says Chan. It covers the bone and is better than nothing, but it doesnt have the bounce and elasticity of natural cartilage, and it tends to degrade relatively quickly.

The most recent research arose, in part, through the work of surgeon and lead author Matthew Murphy, a visiting researcher at Stanford who is now at the University of Manchester.

I never felt anyone really understood how microfracture really worked, Murphy says. I realized the only way to understand the process was to look at what stem cells are doing after microfracture.

For a long time, Chan says, people assumed that adult cartilage did not regenerate after injury because the tissue did not have many skeletal stem cells that could be activated. Working in a mouse model, the team documented that microfracture did activate skeletal stem cells. Left to their own devices, however, those activated skeletal stem cells regenerated fibrocartilage in the joint.

But what if the healing process after microfracture could be steered toward development of cartilage and away from fibrocartilage?

The researchers knew that as bone develops, cells must first go through a cartilage stage before turning into bone. They had the idea that they might encourage the skeletal stem cells in the joint to start along a path toward becoming bone, but stop the process at the cartilage stage.

The researchers used a powerful molecule called bone morphogenetic protein 2 (BMP2) to initiate bone formation after microfracture, but then stopped the process midway with a molecule that blocked another signaling molecule important in bone formation, called vascular endothelial growth factor (VEGF).

What we ended up with was cartilage that is made of the same sort of cells as natural cartilage with comparable mechanical properties, unlike the fibrocartilage that we usually get, Chan says. It also restored mobility to osteoarthritic mice and significantly reduced their pain.

As a proof of principle that this might also work in humans, the researchers transferred human tissue into mice that were bred to not reject the tissue, and were able to show that human skeletal stem cells could be steered toward bone development but stopped at the cartilage stage.

The next stage of research is to conduct similar experiments in larger animals before starting human clinical trials. Murphy points out that because of the difficulty in working with very small mouse joints, there might be some improvements to the system they could make as they move into relatively larger joints.

The first human clinical trials might be for people who have arthritis in their fingers and toes. We might start with small joints, and if that works we would move up to larger joints like knees, Murphy says.

Right now, one of the most common surgeries for arthritis in the fingers is to have the bone at the base of the thumb taken out. In such cases we might try this to save the joint, and if it doesnt work we just take out the bone as we would have anyway. Theres a big potential for improvement, and the downside is that we would be back to where we were before.

One advantage of their discovery is that the main components of a potential therapy are approved as safe and effective by the FDA, says co-senior author Michael Longaker, professor of surgery.

BMP2 has already been approved for helping bone heal, and VEGF inhibitors are already used as anti-cancer therapies, he says. This would help speed the approval of any therapy we develop.

Joint replacement surgery has revolutionized how doctors treat arthritis and is very common: By age 80, 1 in 10 people will have a hip replacement and 1 in 20 will have a knee replaced. But such joint replacement is extremely invasive, has a limited lifespan and is performed only after arthritis hits and patients endure lasting pain.

The researchers say they can envision a time when people are able to avoid getting arthritis in the first place by rejuvenating their cartilage in their joints before it is badly degraded.

One idea is to follow a Jiffy Lube model of cartilage replenishment, Longaker says. You dont wait for damage to accumulateyou go in periodically and use this technique to boost your articular cartilage before you have a problem.

The work appears in the journal Nature Medicine.

Support for the research came from the National Institutes of Health, the California Institute for Regenerative Medicine, the Oak Foundation, the Pitch Johnson Fund, the Gunn/Olivier Research Fund, the Stinehart/Reed Foundation, The Siebel Foundation, the Howard Hughes Medical Institute, the German Research Foundation, the PSRF National Endowment, National Center for Research Resources, the Prostate Cancer Research Foundation, the American Federation of Aging Research, and the Arthritis National Research Foundation.

Source: Stanford University

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