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Johns Hopkins Orthopaedic Surgery - To Halt Osetoarthritis Progression
Johns Hopkins Orthopaedic Surgery Winter 2014
To Halt Osetoarthritis Progression
Date: February 3, 2014
Xu Cao says the lack of effective drugs or a complete understanding of the underlying process that causes OA to progress led his group to search for a different underlying cause.
The prevailing theory on the development of osteoarthritis suggests that unstable mechanical pressure on the joints leads to more and more harm to the cartilage. John Hopkins scientists, however, have turned that view inside out. Instead of seeing the problem primarily as the cartilage that cushions joints, they now have evidence that the bone underneath the cartilage is also a key player and exacerbates the damage. And 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.
The new theory, reported in Nature Medicine, suggests that initial harm to the cartilage causes the bone underneath it to build surplus bone that in turn stretches the cartilage above and speeds its decline.
“We began to think of cartilage and subchondral bone as functioning as a single unit,” says Xu Cao, director of the Center for Musculoskeletal Research in the Department of Orthopaedic Surgery. “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 anterior cruciate ligament tears, 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 recruited stem cells to the site so that they could create new bone to fill the holes. Cao calls these pockets of new bone formation “osteoid islets.”
But the bone building and the bone destruction processes were not coordinated in the mice, and 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 osteoarthritis, as confirmed in a computer simulation of the human knee.
The team then tried several methods to block the activity of TGF-beta1. When a TGF-beta1 inhibitor drug was given intravenously, the subchondral bone improved significantly, but the cartilage cap deteriorated further. However, when a different inhibitor of TGF-beta1, an antibody against it, 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,” says Cao. “We are already working to develop a clinical trial to test the efficacy of locally applied TGF-beta1 antibodies in human patients at early stages of the disease.” If successful, their nonsurgical treatment could make osteoarthritis halt in its tracks, he says.