Mice lacking oncostatin m receptor expression show reduced synovial inflammation and cartilage damage, but increased bone loss in response to joint injury

Purpose: Regardless of the inciting event, mild inflammation within the synovium, progressive loss of articular cartilage, osteophyte formation and accrual of subchondral bone are characteristic features of osteoarthritis (OA). The cytokine oncostatin M (OSM) is found at elevated levels in human OA synovial fluid and is a candidate for contributing to OA pathogenesis. In synovial fibroblasts and osteoblasts OSM, signaling via its ligand-specific receptor, OSMR, induces expression of pro-inflammatory cytokines such as IL-6, cartilage degrading enzymes and the pro-osteoclastic factor, RANKL. We have also shown that OSM can augment IL-1 actions in synovial fibroblasts by increasing expression of IL-1R1.We hypothesized that, mice lacking expression of OSMR (OSMR KO mice) may be protected from injury-induced osteoarthritic-joint damage. Methods: 12-week old male OSMR KO mice and their wildtype littermates (OSMR WT) underwent surgical transection of the medial meniscotibial ligament (DMM) or sham surgery on the right knee. Hind limbs were collected and analysed at 8 weeks post-surgery. Bone structure was analysed by ex-vivo micro-CT (Skyscan). Aggrecan loss and cartilage damage were assessed according to the OARSI histologic scoring scheme. Synovial inflammation was assessed using a modified scoring scheme typically used for inflammatory arthritis. Statistics: 2-way ANOVA, Sidak multiple comparisons post-hoc tests. Results: At 8 weeks post-surgery in OSMR WT mice, increased loading within the medial compartment of the tibia resulted in a focal increase in medial subchondral bone (bone volume/tissue volume, BV/TV) in DMM tibiae compared to sham tibiae. In contrast, OSMR KO mice showed reduced BV/TV at this site in DMM tibiae compared to sham tibiae (p<0.01). Furthermore, tibial metaphyseal trabecular BV/TV was also reduced in OSMR KO DMM tibiae compared to sham tibiae (p<0.01); this was not observed in OSMR WT mice. Although OSMR KO mice showed similar levels of DMM-induced aggrecan loss compared to OSMR WT mice, structural cartilage damage was reduced (p<0.05) in the OSMR KO mice. Furthermore OSMR KO mice also showed reduced synovial inflammation (p<0.05) compared to OSMR WT mice. Conclusions: Together our data indicate that OSM signalling via OSMR contributes to synovial inflammation and cartilage destruction in response to joint injury. Surprisingly, OSMR KO mice showed a reduction in subchondral bone and metaphyseal trabecular bone in DMM-tibiae compared to sham tibiae suggesting that OSMR-mediated signalling is also critical in limiting bone loss in these conditions.