Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and...

SH3 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).

First, 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.

SH3BP2 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.

SH3BP2 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.