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Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets

  • OSTEOARTHRITIS (MB GOLDRING, SECTION EDITOR)
  • Published:
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Abstract

More than two decades of research has revealed a combination of proteases that determine cartilage degradation in osteoarthritis. These include metalloproteinases, which degrade the major macromolecules in cartilage, aggrecan and type II collagen, serine proteases, and cysteine proteases, for example cathepsin K. This review summarizes the function of proteases in osteoarthritis progression, as revealed by studies of genetically engineered mouse models. A brief overview of the biochemical characteristics and features of several important proteases is provided, with the objective of increasing understanding of their function. Published data reveal at least three enzymes to be major targets for osteoarthritis drug development: ADAMTS-5, MMP-13, and cathepsin K. In surgical models of osteoarthritis, mice lacking these enzymes are protected from cartilage damage and, to varying degrees, from bone changes. In-vivo studies targeting these proteases with selective small-molecule inhibitors have been performed for a variety of animal models. Mouse models will provide opportunities for future tests of the therapeutic effect of protease inhibitors, both on progression of structural damage to the joint and on associated pain.

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Acknowledgments

Rachel E. Miller is supported by an Arthritis Foundation Post-Doctoral Fellowship. Anne-Marie Malfait is supported by grant R01AR060364 from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases. The funding agencies had no part in the preparation of this manuscript.

The articles cited in this review were selected from the authors’ personal libraries of articles and from PubMed searches using the keywords “osteoarthritis”, “proteases”, “inhibitors”, and “animal models”. Selections were made on the basis of the expert opinions of the authors. Searches were performed through December 2012.

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Conflict of interest

Anne-Marie Malfait was previously employed by Pfizer. Micky D. Tortorella was previously employed by Pfizer. Anne-Marie Malfait is an associate editor of Osteoarthritis and Cartilage (Elsevier). Rachel E. Miller declares that she has no conflict of interest. Yongzhi Lu declares that he has no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Medicine, Section of Rheumatology, and Department of Biochemistry, Rush University Medical Center, 1611 W. Harrison St., Suite 510, Chicago, IL, 60612, USA

    Rachel E. Miller & Anne-Marie Malfait

  2. Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Yongzhi Lu & Micky D. Tortorella

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  1. Rachel E. Miller
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  2. Yongzhi Lu
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  4. Anne-Marie Malfait
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Correspondence to Anne-Marie Malfait.

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This article is part of the Topical Collection on Osteoarthritis

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Miller, R.E., Lu, Y., Tortorella, M.D. et al. Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets. Curr Rheumatol Rep 15, 350 (2013). https://doi.org/10.1007/s11926-013-0350-2

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