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

Abstract

ObjectiveProteinase-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.MethodsOA 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.ResultsOsteophytes 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.ConclusionsThis 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.

Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis

“…Indeed, we previously showed that the BV/TV decreased early after DMM, at week 4 but not at weeks 6 and 9 23. To the difference of Stattic, MR16-1 significantly decreased the extent of synovitis, which occurred early in the DMM model 29 34. This suggests that MR-16 might act through other pathways than Stat3 in the synovium tissue.…”

Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease

“…The use of the micro-CT technique to assess therapeutic interventions is already being applied in other disease states (Bougioukli et al, 2015; Rusckowski et al, 2016). Similarly, micro-CT imaging is already being relied on in pre-clinical transgenic models involving genetic alterations and transcriptional modifications (Huesa et al, 2015; Keller et al, 2013). This novel technology provides high sensitivity in lesion detection with a spatial resolution of 19-μm isotropic voxel size.…”

Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics

“…PAR2‐deficient mice also showed protection from cartilage damage in the DMM model of OA (Ferrell et al ., ; Amiable et al ., ; Jackson et al ., ), which has limited inflammation. Further studies on murine DMM indicated that PAR2 deficiency delayed osteophyte maturation (Huesa et al ., ), which reflects the previously observed delay in callus formation during bone fracture repair (Georgy et al ., ; O'Neill et al ., ). This suggests a role for PAR2 in driving pathogenic chondrocyte differentiation and/or maturation, separate from its pro‐inflammatory action.…”