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

William R. Ferrell, Elizabeth B. Kelso, John C. Lockhart, Robin Plevin, Iain B. McInnes

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2051-2054
JournalAnnals of the Rheumatic Diseases
Volume69
Issue number11
DOIs
Publication statusPublished - Nov 2010

Press / Media

University works on arthritis research

John Lockhart & William R. Ferrell

1/03/16

1 item of Media coverage

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£1.2m to research new treatments for Osteoarthritis

John Lockhart

1/01/13

1 item of Media coverage

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£1.2m grant for Osteoarthritis research

John Lockhart

1/01/13

1 item of Media coverage

Press/Media: Research

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