1. University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, 3052 Victoria, Australia
2. Raymond Purves Bone and Joint Research Laboratories, University of Sydney, Royal North Shore Hospital, St. Leonards, 2065 New South Wales, Australia
3. Murdoch Childrens Research Institute, Department of Surgery, Royal Children's Hospital, Parkville, 3052 Victoria, Australia
4. Reid Rheumatology Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 Victoria, Australia
5. Johnson & Johnson Pharmaceutical Research and Development, La Jolla, San Diego, California 92121, USA

Correspondence to: Amanda J. Fosang¹ Correspondence and requests for materials should be addressed to A.J.F. (Email: amanda.fosang@mcri.edu.au).

Abstract

Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more 'aggrecanases' from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs¹) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity^{2, 3, 4, 5}. However, they are not thought to be the primary aggrecanases because ADAMTS1 null mice are not protected from experimental arthritis⁶, and cleavage by ADAMTS8 and 9 is highly inefficient. Although ADAMTS4 and 5 are expressed in joint tissues^{7, 8, 9, 10, 11, 12, 13}, and are known to be efficient aggrecanases in vitro, the exact contribution of these two enzymes to cartilage pathology is unknown. Here we show that ADAMTS5 is the major aggrecanase in mouse cartilage, both in vitro and in a mouse model of inflammatory arthritis. Our data suggest that ADAMTS5 may be a suitable target for the development of new drugs designed to inhibit cartilage destruction in arthritis, although further work will be required to determine whether ADAMTS5 is also the major aggrecanase in human arthritis.

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