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

Huesa, C. et al. (2016) Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology. Annals of the Rheumatic Diseases, 75(11), pp. 1989-1997. (doi:10.1136/annrheumdis-2015-208268) (PMID:26698846) (PMCID:PMC5099200)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Ferrell, Professor William and Goodyear, Professor Carl and Kurowska-Stolarska, Dr Mariola and Bennett, Miss Louise
Authors: Huesa, C., Ortiz, A. C., Dunning, L., McGavin, L., Bennett, L., McIntosh, K., Crilly, A., Kurowska-Stolarska, M., Plevin, R., van ‘t Hof, R. J., Rowan, A. D., McInnes, I. B., Goodyear, C. S., Lockhart, J. C., and Ferrell, W. R.
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:23 December 2016
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Annals of the Rheumatic Diseases 75(11):1989-1997
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
595151Lessening the burden of osteoarthritis: elucidating the pathogenic role of the PAR-2 Pathway.William FerrellArthritis Research UK (ARUK)20199III -IMMUNOLOGY