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Matrix Metalloproteinases Are Not Essential for Aggrecan Turnover during Normal Skeletal Growth and Development

Christopher B. Little, Clare T. Meeker, Rosalind M. Hembry, Natalie A. Sims, Kate E. Lawlor, Sue B. Golub, Karena Last, and Amanda J. Fosang^*

Arthritis Research Group, University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia

Received 22 October 2004/ Returned for modification 9 December 2004/ Accepted 7 January 2005

The growth plate is a transitional region of cartilage and highly diversified chondrocytes that controls long bone formation. The composition of growth plate cartilage changes markedly from the epiphysis to the metaphysis, notably with the loss of type II collagen, concomitant with an increase in MMP-13; type X collagen; and the C-propeptide of type II collagen. In contrast, the fate of aggrecan in the growth plate is not clear: there is biosynthesis and loss of aggrecan from hypertrophic cartilage, but the mechanism of loss is unknown. All matrix metalloproteinases (MMPs) cleave aggrecan between amino acids N₃₄₁ and F₃₄₂ in the proteinase-sensitive interglobular domain (IGD), and MMPs in the growth plate are thought to have a role in aggrecanolysis. We have generated mice with aggrecan resistant to proteolysis by MMPs in the IGD and found that the mice develop normally with no skeletal deformities. The mutant mice do not accumulate aggrecan, and there is no significant compensatory proteolysis occurring at alternate sites in the IGD. Our studies reveal that MMP cleavage in this key region is not a predominant mechanism for removing aggrecan from growth plate cartilage.

Present address: Raymond Purves Bone and Joint Research Laboratories, Level 5 University Clinic—B26, University of Sydney at the Royal North Shore Hospital, St. Leonards 2065, New South Wales, Australia.

Present address: School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom.

Present address: Department of Medicine at St. Vincent's Hospital, University of Melbourne and St. Vincent's Institute, Fitzroy 2065, Australia.

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