Article Text

other Versions

PDF
Concise report
Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis
  1. William R Ferrell1,
  2. Elizabeth B Kelso1,
  3. John C Lockhart2,
  4. Robin Plevin3,
  5. Iain B McInnes4
  1. 1Division of Integrative Biology, University of Glasgow, Glasgow, UK
  2. 2School of Science, University of the West of Scotland, Paisley, UK
  3. 3Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK
  4. 4Division of Immunology Infection and Inflammation, University of Glasgow, UK
  1. Correspondence to Professor William R Ferrell, Room 407, Level 4, McGregor Building, Western Infirmary, Dumbarton Road, Glasgow, Scotland G11 6NT, UK; W.Ferrell{at}bio.gla.ac.uk

Abstract

Objective Osteoarthritis is a global clinical challenge for which no effective disease-modifying agents currently exist. This study identified protease-activated receptor 2 (PAR-2) as a novel pathogenic mechanism and potential therapeutic target in osteoarthritis.

Methods Experimental osteoarthritis was induced in wild-type and PAR-2-deficient mice by sectioning the medial meniscotibial ligament (MMTL), leading to the development of a mild arthropathy. Cartilage degradation and increased subchondral bone formation were assessed as indicators of osteoarthritis pathology.

Results Four weeks following MMTL section, cartilage erosion and increased subchondral bone formation was evident in wild-type mice but was substantially reduced in PAR-2-deficient mice. Crucially, the therapeutic inhibition of PAR-2 in wild-type mice, using either a PAR-2 antagonist or a monoclonal antibody targeting the protease cleavage site of PAR-2, was also equally effective at reducing osteoarthritis progression in vivo. PAR-2 was upregulated in chondrocytes of wild-type but not sham-operated mice. Wild-type mice showed further joint degradation 8 weeks after the induction of osteoarthritis, but PAR-2-deficient mice were still protected.

Conclusions The substantial protection from pathology afforded by PAR-2 deficiency following the induction of osteoarthritis provides proof of concept that PAR-2 plays a key role in osteoarthritis and suggests this receptor as a potential therapeutic target.

Statistics from Altmetric.com

Footnotes

  • Funding Financial support was received from the Arthritis Research UK (17728, 18901) and the Carnegie Trust.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.