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Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

Lookup NU author(s): Emeritus Professor Drew Rowan, Professor Iain McInnes, Dr Carl Goodyear

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Abstract

Objective Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.Methods OA was induced in wild-type (WT) and PAR2-deficient (PAR2(-/-)) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2(-/-) mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain.Results Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2(-/-) mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2(-/-) mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2(-/-) mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone.Conclusions This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.


Publication metadata

Author(s): Huesa C, Ortiz AC, Dunning L, McGavin L, Bennett L, McIntosh K, Crilly A, Kurowska-Stolarska M, Plevin R, van't Hof RJ, Rowan AD, McInnes IB, Goodyear CS, Lockhart JC, Ferrell WR

Publication type: Article

Publication status: Published

Journal: Annals of Rheumatic Diseases

Year: 2016

Volume: 75

Issue: 11

Pages: 1989-1997

Print publication date: 01/11/2016

Online publication date: 23/12/2015

Acceptance date: 24/11/2015

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Publishing Group

URL: http://dx.doi.org/10.1136/annrheumdis-2015-208268

DOI: 10.1136/annrheumdis-2015-208268


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