Proteinase-activated Receptor-2 Gene Disruption Limits the Effect of Osteoarthritis on Cartilage in Mice: A Novel Target in Joint Degradation

Abstract

Objective.Evidence indicates that proteinase-activated receptor (PAR)-2 participates in the degradative processes of human osteoarthritis (OA). We evaluated the in vivo effect of PAR-2 on articular lesions in a PAR-2-knockout (KO) mouse model of OA.Methods.OA was surgically induced by destabilization of the medial meniscus of the right knee in C57Bl/6 wild-type (WT) and PAR-2 KO mice. Knee swelling was measured throughout the duration of the study (8 weeks postsurgery) and histologic evaluation of cartilage was done to assess structure, cellularity, matrix staining, and remodeling in the deep zone. Morphometric analysis of subchondral bone was also performed.Results.Data showed significant knee swelling in the operated WT mice immediately following surgery, which increased with time (8 weeks post-surgery). Knee swelling was significantly lower (p ≤ 0.0001) in PAR-2 KO mice than in WT mice at both 4 and 8 weeks postsurgery. Cartilage damage was found in both operated WT and PAR-2 KO mice; however, lesions were significantly less severe (global score; p ≤ 0.05) in the PAR-2 KO mice at 4 weeks postsurgery. Operated WT mice showed reduced subchondral bone surface and trabecular thickness with significance reached at 4 weeks (p ≤ 0.03 and p ≤ 0.05, respectively), while PAR-2 KO mice demonstrated a gradual increase in subchondral bone surface with significance reached at 8 weeks (p ≤ 0.007).Conclusion.We demonstrated the in vivo implication of PAR-2 in the development of experimental OA, thus confirming its involvement in OA joint structural changes and reinforcing the therapeutic potential of a PAR-2 antagonist for treatment of OA.