Depletion of Protease-Activated Receptor 2 but Not Protease-Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms

Objective. To explore the involvement of proteaseactivated receptor 1 (PAR-1) and PAR-2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR-1 or PAR-2 in mice. Methods. OA was induced in the joints of wildtype (WT), PAR-1 /, PAR-1 /, and PAR-2 / mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks postDMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/ activity were studied in cultures of mouse femoral head tissue with or without interleukin-1 (IL-1 ). At 1 week post-DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription-polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry. Results. Deletion of PAR-2, but not that of PAR-1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1 -induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post-DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4 T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR-2 / mice compared to PAR-1 / and WT mice. Conclusion. Deletion of PAR-2, but not that of PAR-1, results in a significant decrease in DMMinduced cartilage damage. The chondroprotection in PAR-2 / mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.