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  • Review Article
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The role of ADAMTS-7 and ADAMTS-12 in the pathogenesis of arthritis

Nature Clinical Practice Rheumatology volume 5, pages 38–45 (2009)Cite this article

Abstract

Loss of articular cartilage caused by extracellular matrix breakdown is the hallmark of arthritis. Degradative fragments of cartilage oligomeric matrix protein (COMP) have been observed in arthritic patients. ADAMTS-7 and ADAMTS-12, two members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, have been associated with COMP degradation in vitro, and are significantly overexpressed in the cartilage and synovium of patients with rheumatoid arthritis. Recent studies have demonstrated the importance of COMP degradation by ADAMTS-7 and ADAMTS-12. Specifically, the size of COMP fragments generated by ADAMTS-7 or ADAMTS-12 is similar to that of COMP-degradative fragments seen in arthritic patients. In addition, antibodies against ADAMTS-7 or ADAMTS-12 dramatically inhibit tumor necrosis factor-induced and interleukin-1β-induced COMP degradation in cartilage explants. Furthermore, suppression of ADAMTS-7 or ADAMTS-12 expression using the small interfering RNA silencing approach in human chondrocytes markedly prevents COMP degradation. COMP degradation mediated by ADAMTS-7 and ADAMTS-12 is inhibited by α2-macroglobulin. More significantly, granulin-epithelin precursor, a newly characterized chondrogenic growth factor, disturbs the interaction between COMP and ADAMTS-7 and ADAMTS-12, preventing COMP degradation by these enzymes. This Review summarizes the evidence demonstrating that ADAMTS-7 and ADAMTS-12 are newly identified enzymes responsible for COMP degradation in arthritis, and that α2-macroglobulin and granulin-epithelin precursor represent their endogenous inhibitors.

Key Points

  • ADAMTS-7 and ADAMTS-12, two members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, associate with and degrade cartilage oligomeric matrix protein (COMP) in vitro, and are significantly induced in the cartilage and synovium of patients with rheumatoid arthritis

  • The size of COMP fragments generated by ADAMTS-7 or ADAMTS-12 is similar to that of COMP-degradative fragments seen in arthritic patients

  • Blockade of ADAMTS-7 and ADAMTS-12 activity by specific antibodies or suppression of ADAMTS-7 and ADAMTS-12 expression by the small interfering RNA silencing approach dramatically inhibits tumor necrosis factor-induced and interleukin-1β-induced COMP degradation

  • ADAMTS-7-mediated and ADAMTS-12-mediated COMP degradation is inhibited by α2-macroglobulin

  • Granulin-epithelin precursor, a newly identified chondrogenic growth factor, disturbs the interaction between COMP and ADAMTS-7 and ADAMTS-12, and prevents COMP degradation by these enzymes

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Figure 1: Domain structure and organization of COMP.
Figure 2: Domain structure and organization of ADAMTS-7 and ADAMTS-12.
Figure 3: A diagram of ADAMTS-7 and ADAMTS-12 cleavage of COMP and inhibition of ADAMTS-7 and ADAMTS-12 by α2M and GEP.

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Acknowledgements

Owing to space constraints, some of the primary research contributions to the field have not been included.

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  1. Department of Orthopedic Surgery, New York University Medical Center, Room 1608, HJD, 301 East 17th Street, New York, NY 10003, USA chuanju.liu@med.nyu.edu

Authors and Affiliations

  1. C-J Liu is an Associate Professor of Orthopedic Surgery and Cell Biology at New York University School of Medicine, New York, NY, USA.,

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Liu, CJ. The role of ADAMTS-7 and ADAMTS-12 in the pathogenesis of arthritis. Nat Rev Rheumatol 5, 38–45 (2009). https://doi.org/10.1038/ncprheum0961

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