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

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.

• Authors: William R Ferrell, Elizabeth B Kelso, John C Lockhart, Robin Plevin, Iain B McInnes
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 69 Issue 11 Pg. 2051-4 (Nov 2010) ISSN: 1468-2060 [Electronic] England
• PMID: 20584806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, PAR-2

Topics

• Animals
• Arthritis, Experimental (metabolism, pathology)
• Cartilage, Articular (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoarthritis (metabolism, pathology)
• Receptor, PAR-2 (deficiency, physiology)
• Signal Transduction (physiology)