Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis

Ferrell, W.R., Kelso, E.B., Lockhart, J.C., Plevin, R. and McInnes, I.B. (2010) Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis. Annals of the Rheumatic Diseases, 69(11), pp. 2051-2054. (doi:10.1136/ard.2010.130336) (PMID:20584806)

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Publisher's URL: http://dx.doi.org/10.1136/ard.2010.130336

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Ferrell, Professor William
Authors: Ferrell, W.R., Kelso, E.B., Lockhart, J.C., Plevin, R., and McInnes, I.B.
Subjects:Q Science > QR Microbiology > QR180 Immunology
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Annals of the Rheumatic Diseases
Publisher:B M J Group
ISSN:0003-4967
ISSN (Online):1468-2060
Published Online:01 January 2010
Copyright Holders:Copyright © 2010 BMJ
First Published:First published in Annals of the Rheumatic Diseases
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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