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.
This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
Statistics from Altmetric.com
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Handling editor Tore K Kvien
Contributors CH: design of work, acquisition, analysis and interpretation of the majority of the data. Manuscript draft and corrections. RBvH: conception of project. Intellectual contribution to acquisition, analysis and interpretation of data. Manuscript input and final approval. JCL: conception of project. Contributions to design and interpretation. Manuscript draft, corrections and final approval. LD, ARO, LM, LB and KM: contribution to experimental work. AC and MK-S: intellectual contribution to experimental design. RP and ADR: conception of project. Manuscript corrections and final approval. CSG and IBM: intellectual contribution to experimental design and interpretation of data. Manuscript corrections and final approval. WRF: lead in conception of work, design and interpretation of experiments. Manuscript draft, corrections and final approval.
Funding This research was supported (CH, LD) by an Arthritis Research UK programme grant (20199). LD was also supported by the Carnegie Trust for the Universities of Scotland. MK-S was supported by Arthritis Research UK Career Development Fellowship. AO and LM were supported by University of the West of Scotland studentships. LB was supported by Glasgow Orthopaedic Research Charitable Trust.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.