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

Abstract

Objective SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. The purpose of this study was to investigate the role of SH3BP2 in arthritis in human TNF-α transgenic (hTNFtg) and collagen-induced arthritis (CIA) models. Methods First, SH3BP2-deficient (Sh3bp2–/–) and wild-type (Sh3bp2+/+) mice were crossed with hTNFtg mice. Inflammation and bone loss were examined by clinical inspection and histological and micro-CT analyses. Osteoclastogenesis was evaluated with primary bone marrow-derived M-CSF-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 ELISA. Lymph node cell responses to CII were also determined. Results SH3BP2-deficiency did not alter the severity of joint swelling but suppressed bone erosion in the hTNFtg model. Bone loss of talus and tibia was prevented in Sh3bp2–/–/hTNFtg mice compared to Sh3bp2+/+/hTNFtg mice. RANKL- and TNF-α-induced osteoclastogenesis was suppressed in Sh3bp2–/– BMM cultures. NFATc1 nuclear localization in response to TNF-α was decreased in Sh3bp2–/– BMMs compared to Sh3bp2+/+ BMMs. In the CIA model, SH3BP2-deficiency suppressed the incidence of arthritis, which was associated with decreased anti-CII antibody production, while the antigen-specific T-cell responses in lymph nodes were not significantly different between Sh3bp2+/+ and Sh3bp2–/– mice. Conclusion SH3BP2-deficiency prevents bone loss via impaired osteoclastogenesis in the hTNFtg model and suppresses the induction of arthritis via decreased autoantibody production in the CIA model. Therefore, SH3BP2 could be a therapeutic target for rheumatoid arthritis.

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

“…(32)(33)(34) In contrast, loss-of-function of SH3BP2 has been shown to protect against inflammatory bone loss in mouse models of RA. (39) In this study, we showed that the SH3BP2-SYK pathway, which is the pathogenic pathway responsible for the rare craniofacial disorder cherubism, is also critically involved in the regulation of alveolar bone resorption in a ligature-induced mouse periodontitis model. Therefore, the current study provides a new example for the concept that studying molecular defects in rare craniofacial diseases can result in a better understanding of the basic pathology of more common diseases and lead to opportunities for novel treatment strategies.…”

“…Indeed, SH3BP2-deficient osteoclast progenitors that are stimulated with RANKL are significantly defective in their bone resorption capacity particularly under inflammatory conditions in cell culture, while maintaining the induction of the master osteoclastogenic transcription factor NFATc1. (38,39) They also fail to develop an organized actin cytoskeleton, which is required for sealing zone formation of bone-resorbing osteoclasts. (38,54) In addition, it has been shown that deletion of Sh3bp2 in osteoclast progenitors by LysM-Cre suppressed in vitro osteoclast bone resorption capability.…”

“…conditions and that Sh3bp2 −/− osteoclasts are defective in bone resorption capacity in inflammatory conditions in vitro support this interpretation. (38,39)…”

“…(33)(34)(35) The SH3BP2 gain-of-function mutation also alters the manifestation of autoimmune diseases in mice. (36,37) In contrast, loss-offunction of SH3BP2 suppresses osteoclast function (38,39) and reduces inflammation and joint destruction in mouse models for RA. (39) Thus, investigations from our group have established that SH3BP2 is a regulator of inflammation and osteoclastogenesis and demonstrated that the SH3BP2-SYK axis, as a key signaling pathway in the osteoimmune system, is involved in the pathological mechanisms of common inflammatory arthritis beyond its role in a rare craniofacial disorder.…”

Osteoclasts—Key Players in Skeletal Health and Disease

“…However, since cytokines often affect both the inflammatory component and the OC, many experiments need to be interpreted with caution regarding the direct effects of particular pathways on the osteolytic component of disease. The clearest results regarding effects on OC occur when bone loss can be evaluated in the presence of an intact inflammatory response (163–165). For example, NIK-deficient mice have reduced bone erosion in inflammatory arthritis models.…”