Extracellular matrix and pathogenic mechanisms in osteoarthritis

Osteoarthritis (OA) is a heterogeneous condition of joint degeneration characterized by structural changes in extracellular matrices such as subchondral bone and cartilage. Research has identified many diverse ways of initiating OA, varying from mechanical disruption to gene mutations in structural proteins. A frequent end point is cartilage loss, which can occur irrespective of the initiating mechanism. Of the mechanisms responsible for cartilage matrix damage, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 was identified as of key importance in knockout mice, but work with human cartilage has suggested that ADAMTS-4 was also involved. A transgenic mouse expressing aggrecan lacking a key aggrecanase site clearly showed that loss of aggrecan from cartilage was an important step in both inflammatory and trauma-induced joint degeneration. In OA, cartilage chondrocytes show changes in gene expression, and it remains to be resolved if this reflects adaptive responses to changes in biological, physical, and mechanical signaling rather than any form of differentiation.