Address: University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia

E-mail: amanda.fosang@mcri.edu.au

Key Words: Aggrecanase, ADAMTS-5, ADAMTS-4, aggrecanolysis, metalloproteinase, cartilage, arthritis

Publication date: February 5th 2008

Abstract: 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.

Article download: Pages 11-26 (PDF file)

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