The scientists describe their work in this week's Early Edition of the Proceedings of the National Academy of Sciences.
In the study, the team shows how the loss of the protein HMGB2, found in the surface layer of joint cartilage, leads to the progressive deterioration of the cartilage that is the hallmark of osteoarthritis.
"We have found the mechanism that begins to explain how and why aging leads to deterioration of articular cartilage," says Scripps Research Professor Martin Lotz, M.D., a world-renowned arthritis researcher who led the study with Noboru Taniguchi, M.D., Ph.D., a senior research associate in his lab. "Our findings demonstrate a direct link between the loss of this protein and osteoarthritis."
Osteoarthritis typically begins with a disruption of the surface layer of cartilage. The cartilage surface layer, called the superficial zone, is the most important functionally of the four layers of cartilage present in joints. In normal joints the cartilage surface is perfectly smooth, enabling joints to slide across one another without friction. Once the cartilage of the superficial zone starts to deteriorate, though, osteoarthritis sets in, triggering an irreversible process that eventually leads to the loss of underlying layers of cartilage until bone begins to grind painfully against bone. Osteoarthritis most commonly affects the spine, temporomandibular joints, shoulders, hands, hips and knees.
"We knew that the first phase of osteoarthritis is the destruction of cartilage in the superficial zone," says Lotz, who has spent the past five years studying the role of HMGB2 in osteoarthritis. "Now we know that before this layer is destroyed, there is loss of the critical DNA binding protein HMGB2 and that this loss is directly related to aging."
The team found that the protein HMGB2 is uniquely expressed on the surface layer of cartilage in joints, where it supports the survival of chondrocytes, the cells that produce and maintain cartilage. Aging is associated with the loss of HMGB2 and an accompanying reduction or total elimination of chondrocytes in the superficial zone. The scientists provided further links between HMGB2 and osteoarthritis by breeding mice to be genetically deficient in HMGB2; these mice had an earlier and more severe onset of osteoarthritis.