Aggrecanase-mediated cartilage degradation.

Increasing evidence is accumulating for the importance of the aggrecanases ADAMTS-4 and ADAMTS-5 in cartilage degradation in arthritis. Recent work from a number of laboratories has begun to provide insight into the regulation of the expression and activity of these proteins and the molecular basis of their role in aggrecan catabolism. Recombinant ADAMTS-4 and ADAMTS-5 cleave aggrecan at five distinct sites along the core protein and aggrecan fragments generated by cleavage at all of these sites have been identified in cartilage explants undergoing matrix degradation. This proteolytic activity of the aggrecanases can be modulated by several means, including altered expression, activation by proteolytic cleavage at a furin-sensitive site, binding to the aggrecan substrate through the C-terminal thrombospondin motif, activation through post-translational processing of a portion of the C-terminus and inhibition of activity by the endogenous inhibitor TIMP-3. ADAMTS-4 and ADAMTS-5 activity is detected in joint capsule and synovium in addition to cartilage, and may be upregulated in arthritic synovium at either the message level or through post-translational processing. Additional substrates have now been identified, including the chondroitin-sulfate proteoglycans brevican and versican. Finally, advances are occurring in the development of selective aggrecanase inhibitors designed to serve as therapeutics for the treatment of arthritis.