The Molecular Pathogenesis of Osteoarthritis Project Overview Osteoarthritis is a process of joint cartilage destruction that involves progressive loss/degeneration of the articular cartilage, subchondral sclerosis and osteophyte formation. Several key mechanisms have been identified that either initiate or contribute to the degeneration, including injury, aging, obesity/type 2 diabetes and genetics. It is widely held that contributing to the degenerative process is the dysfunction of articular chondrocytes, characterized by inappropriate hypertrophic differentiation, loss of matrix production, up-regulation of matrix-degrading enzymes and ultimate apoptosis. Using mutant mouse models supporting loss or gain of signaling function, we have discovered that alterations in several key pathways lead to this aberrant behavior in chondrocytes, including loss of TGF-beta signaling and increased Wnt/beta-catenin signaling. By understanding the contribution of signaling pathways to osteoarthritic degeneration, we can begin to develop novel therapies that specifically target signaling function in the articular chondrocyte. Such advances would have immediate clinical impact since the only therapies for osteoarthritis currently are palliative: anti-inflammatory medications and joint replacement.