Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis

  • A Corrigendum to this article was published on 01 March 2007

Abstract

Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific ‘aggrecanase’ site in human osteoarthritic cartilage1,2; this cleavage can be performed by several members of ADAMTS family of metalloproteases3,4,5,6,7,8,9. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary ‘aggrecanase’ responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.

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Figure 1: Targeted disruption of the murine ADAMTS5 gene.
Figure 2: Immunohistochemical localization of the aggrecanase-generated TEGE373 neoepitope in growth plates of wild-type, ADAMTS4-/- and ADAMTS5-/- mice.
Figure 3: Histological scores of joints 4 and 8 weeks after induction of joint instability.
Figure 4: Proteoglycan release from articular cartilage from wild-type and ADAMTS5 knockout mice.

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Acknowledgements

The authors would like to acknowledge M. Jin and X.-Y. Tan for generation of the monoclonal antibody AGG-C1. We also acknowledge the assistance of W. Kuang, M. Liang, K. Shih, J. Tavares, K. Tomkinson and T. Crawford, and the Bioresources staff at Wyeth.

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Correspondence to Elisabeth A. Morris.

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This file contains Supplementary Methods, Supplementary Results 1-4 and also contains additional references. (DOC 26 kb)

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Glasson, S., Askew, R., Sheppard, B. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005). https://doi.org/10.1038/nature03369

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