ADAMTS-5: the story so far.

The recent discovery of ADAMTS-5 as the major aggrecanase in mouse cartilage came as a surprise. A great deal of research had focused on ADAMTS-4 and much less was known about the regulation, expression and activity of ADAMTS-5. Two years on, it is still not clear whether ADAMTS-4 or ADAMTS-5 is the major aggrecanase in human cartilage. On the one hand there are in vitro studies using siRNA, neutralising antibodies and immunoprecipitation with anti-ADAMTS antibodies that suggest a significant role for ADAMTS-4 in aggrecanolysis. On the other hand, ADAMTS-5 (but not ADAMTS-4)-deficient mice are protected from cartilage erosion in models of experimental arthritis, and recombinant human ADAMTS-5 is substantially more active than ADAMTS-4. The activity of both enzymes is modulated by C-terminal processing, which occurs naturally in vivo. The most interesting finding to emerge from our comparison of ADAMTS-5 and ADAMTS-4 is that in terms of gene regulation, these two enzymes are the antitheses of each other. In most cases, ADAMTS-5 is constitutively expressed in human chondrocytes and synovial fibroblasts, whereas ADAMTS-4 expression is induced by proinflammatory cytokines. This paper reviews the data on ADAMTS-5 so far. It represents a snapshot in time of a field that is fast-moving and very exciting.