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ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro


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 activity2,3,4,5. 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 tissues7,8,9,10,11,12,13, 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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Figure 1: Generation of the ADAMTS4 and ADAMTS5 Δ-cat mice.
Figure 2: IL-1α stimulation of aggrecan release in cartilage explant cultures.
Figure 3: Antigen-induced arthritis in control and ADAMTS5-deficient mice.

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The authors are grateful to Johnson & Johnson Pharmaceutical Research and Development (San Diego) for donating the floxed mice. We thank E. Arner and M. Tortorella for providing the anti-AGEG antibody. We also gratefully acknowledge the mouse husbandry support provided by the Disease Models Unit of the Murdoch Childrens Research Institute. The work was funded by the National Health and Medical Research Council (Australia), and the Murdoch Childrens Research Institute.

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Correspondence to Amanda J. Fosang.

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Stanton, H., Rogerson, F., East, C. et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434, 648–652 (2005).

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