Successful tests on mice, conducted by scientists at Johns Hopkins University, have added credibility to a new theory on the cause of osteoarthritis (OA). Test results are published in the May 19 issue of Nature Magazine. The investigators write that instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, they now have evidence that the bone underneath the cartilage is a key player and causes some of the damage. In a proof-of-concept experiment, they found that blocking the action of a critical bone regulation protein in mice halts progression of the disease.
First, the prevailing theory. This holds that the development of osteoarthritis is caused by pressure on the joints leading to damage to the cartilage. This degeneration is most frequently associated with instability in the load-bearing joints of the knee and hip caused by injury or strain. Athletes, overweight people and people whose muscles are weakened by aging are at highest risk of developing OA. As the cartilage wears away or is further damaged, patients experience severe pain. The only treatment option left is a knee or hip replacement.
The new theory suggests that initial damage to the cartilage causes the bone underneath it to begin building surplus bone. Instead of solving the problem, the extra bone stretches the cartilage above it and speeds its decline. “If there is something wrong with the leg of your chair and you try to fix it by replacing the cushion, you haven’t solved the problem, ” says Xu Cao, Ph.D., director of the Center for Musculoskeletal Research in the Department of Orthopaedic Surgery at the Johns Hopkins University School of Medicine. “We think that the problem in OA is not just the cartilage ‘cushion, ‘ but the bone underneath.”
Cao and his team began to think of cartilage and the bone underneath it as functioning as a single unit, ” says Cao. “That helped us to see the ways in which the bone was responding to changes in the cartilage and exacerbating the problem.”
Using mice with ACL (anterior cruciate ligament) tears, which are known to lead to OA of the knee, the researchers found that, as soon as one week after the injury, pockets of subchondral bone had been “chewed” away by cells called osteoclasts. This process activated high levels in the bone of a protein called TGF-beta1, which, in turn, recruited stem cells to the site so that they could create new bone to fill the holes.
Unfortunately, the bone building and the bone destruction processes were not coordinated in the mice. The bone building prevailed, placing further strain on the cartilage cap. It is this extraneous bone formation that Cao and his colleagues believe to be at the heart of OA.
When a TGF-beta1 inhibitor drug was injected directly into the subchondral bone, the positive effects were seen in the bone without the negative effects on the cartilage. The same result was also seen when TGF-beta1 was genetically disrupted in the bone precursor cells alone. “Our results are potentially really good news for patients with OA, ” says Cao.
Cao and his associates are now working to develop a clinical trial to test the efficacy of locally applied TGF-beta1 antibodies in human patients at early stages of OA. If successful, their nonsurgical treatment could make OA—and the pain and debilitation it causes—“halt in its tracks, ” he says.
