Review Article | Published:

Proteinases and their receptors in inflammatory arthritis: an overview

Nature Reviews Rheumatology volume 14, pages 170180 (2018) | Download Citation

Abstract

Proteinases are enzymes with established roles in physiological and pathological processes such as digestion and the homeostasis, destruction and repair of tissues. Over the past few years, the hormone-like properties of circulating proteinases have become increasingly appreciated. Some proteolytic enzymes trigger cell signalling via proteinase-activated receptors, a family of G protein-coupled receptors that have been implicated in inflammation and pain in inflammatory arthritis. Proteinases can also regulate ion flux owing to the cross-sensitization of transient receptor potential cation channel subfamily V members 1 and 4, which are associated with mechanosensing and pain. In this Review, the idea that proteinases have the potential to orchestrate inflammatory signals by interacting with receptors on cells within the synovial microenvironment of an inflamed joint is revisited in three arthritic diseases: osteoarthritis, spondyloarthritis and rheumatoid arthritis. Unanswered questions are highlighted and the therapeutic potential of modulating this proteinase–receptor axis for the management of disease in patients with these types of arthritis is also discussed.

Key points

  • Microenvironment proteinase-mediated signalling can have a key role in arthritis

  • Proteinase-mediated activation or silencing of proteinase-activated receptors (PARs), cross-activation of transient receptor potential cation channels and release of complement receptor ligands can regulate pain and inflammation in the joint

  • Proteinases and their receptors, including the PARs, represent promising targets for the treatment of arthritic pain and inflammation

  • Either enzyme-selective or broad-spectrum proteinase inhibitors administered in the restricted environment of the joint space over a programmed time frame could prove of value in treating arthritis

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Acknowledgements

The authors thank Sowmya Viswanathan, Konstantinos Tselios and Alejandro Gómez-Aristizábal at the University Health Network, Toronto, Canada for critical discussions of this manuscript. The authors' ongoing work related to this field of research is supported by the Krembil Foundation (K.O. and V.C.) and the Canadian Institutes of Health Research (E.P.D. and M.D.H.).

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Author notes

    • Morley D. Hollenberg
    •  & Vinod Chandran

    These authors contributed equally: Morley D. Hollenberg, Vinod Chandran.

Affiliations

  1. Centre for Prognosis Studies in Rheumatic Diseases, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

    • Katerina Oikonomopoulou
    •  & Vinod Chandran
  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Eleftherios P. Diamandis
  3. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Eleftherios P. Diamandis
  4. Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada.

    • Eleftherios P. Diamandis
  5. Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.

    • Morley D. Hollenberg
  6. Department of Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.

    • Morley D. Hollenberg
  7. Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Vinod Chandran
  8. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

    • Vinod Chandran

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Contributions

K.O. and V.C. researched the data for this article. All authors wrote this article, made substantial contributions to discussions of content and reviewed or edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vinod Chandran.

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DOI

https://doi.org/10.1038/nrrheum.2018.17