Loss of SH3 Domain–Binding Protein 2 Function Suppresses Bone Destruction in Tumor Necrosis Factor–Driven and Collagen‐Induced Arthritis in Mice

ObjectiveSH3 domain–binding protein 2 (SH3BP2) is a signaling adapter protein that regulates the immune and skeletal systems. The present study was undertaken to investigate the role of SH3BP2 in arthritis using 2 experimental mouse models, i.e., human tumor necrosis factor α–transgenic (hTNF‐Tg) mice and mice with collagen‐induced arthritis (CIA).MethodsFirst, Sh3bp2−/− and wild‐type (Sh3bp2+/+) mice were crossed with hTNF‐Tg mice. Inflammation and bone loss were examined by clinical inspection and histologic and micro−computed tomography analysis, and osteoclastogenesis was evaluated using primary bone marrow–derived macrophage colony‐stimulating factor–dependent macrophages (BMMs). Second, CIA was induced in Sh3bp2−/− and Sh3bp2+/+ mice, and the incidence and severity of arthritis were evaluated. Anti–mouse type II collagen (CII) antibody levels were measured by enzyme‐linked immunosorbent assay, and lymph node cell responses to CII were determined.ResultsSH3BP2 deficiency did not alter the severity of joint swelling but did suppress bone erosion in the hTNF‐Tg mouse model. Bone loss at the talus and tibia was prevented in Sh3bp2−/−/hTNF‐Tg mice compared to Sh3bp2+/+/hTNF‐Tg mice. RANKL‐ and TNFα‐induced osteoclastogenesis was suppressed in Sh3bp2−/− mouse BMM cultures. NF‐ATc1 nuclear localization in response to TNFα was decreased in Sh3bp2−/− mouse BMMs compared to Sh3bp2+/+ mouse BMMs. In the CIA model, SH3BP2 deficiency suppressed the incidence of arthritis and this was associated with decreased anti‐CII antibody production, while antigen‐specific T cell responses in lymph nodes were not significantly different between Sh3bp2+/+ and Sh3bp2−/− mice.ConclusionSH3BP2 deficiency prevents loss of bone via impaired osteoclastogenesis in the hTNF‐Tg mouse model and suppresses the induction of arthritis via decreased autoantibody production in the CIA model. Therefore, SH3BP2 could potentially be a therapeutic target in rheumatoid arthritis.