Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and collagen-induced arthritis in mice.
Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and collagen-induced arthritis in mice.
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DOI：
10.1002/art.38975
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发表时间：
2015-03
影响因子：
13.3
通讯作者：
Ueki, Yasuyoshi
中科院分区：
文献类型：
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作者：
Mukai, Tomoyuki;Gallant, Richard;Ishida, Shu;Kittaka, Mizuho;Yoshitaka, Teruhito;Fox, David A.;Morita, Yoshitaka;Nishida, Keiichiro;Rottapel, Robert;Ueki, Yasuyoshi
SH3BP2 是一种调节免疫和骨骼系统的信号转接蛋白。本研究的目的是在人类 TNF-α 转基因 (hTNFtg) 和胶原诱导的关节炎 (CIA) 模型中研究 SH3BP2 在关节炎中的作用。首先，将 SH3BP2 缺陷型 (Sh3bp2–/–) 和野生型 (Sh3bp2+/+) 小鼠与 hTNFtg 小鼠杂交。通过临床检查、组织学和显微 CT 分析来检查炎症和骨质流失。使用原代骨髓源性 M-CSF 依赖性巨噬细胞 (BMM) 评估破骨细胞生成。其次，在Sh3bp2–/–和Sh3bp2+/+小鼠中诱导CIA，并评估关节炎的发生率和严重程度。通过 ELISA 测定抗小鼠 II 型胶原 (CII) 抗体水平。还测定了淋巴结细胞对 CII 的反应。在 hTNFtg 模型中，SH3BP2 缺陷不会改变关节肿胀的严重程度，但会抑制骨侵蚀。与 Sh3bp2+/+/hTNFtg 小鼠相比，Sh3bp2–/–/hTNFtg 小鼠的距骨和胫骨骨丢失得到了预防。 Sh3bp2–/– BMM 培养物中 RANKL 和 TNF-α 诱导的破骨细胞生成受到抑制。与 Sh3bp2+/+ BMM 相比，Sh3bp2–/– BMM 中 NFATc1 响应 TNF-α 的核定位减少。在 CIA 模型中，SH3BP2 缺陷抑制了关节炎的发生，这与抗 CII 抗体产生减少有关，而 Sh3bp2+/+ 和 Sh3bp2–/– 小鼠之间淋巴结中的抗原特异性 T 细胞反应没有显着差异。在 hTNFtg 模型中，SH3BP2 缺陷通过破骨细胞生成受损来防止骨质流失，在 CIA 模型中通过减少自身抗体产生来抑制关节炎的诱发。因此，SH3BP2可能成为类风湿性关节炎的治疗靶点。
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. 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. 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. 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.
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影响因子：
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作者：
Hayward, Michael D;Jones, Beverly K;Saparov, Arman;Hain, Heather S;Trillat, Anne-Cecile;Bunzel, Michelle M;Corona, Aaron;Li-Wang, Bifang;Strenkowski, Bryan;Giordano, Caroline;Shen, Hai;Arcamone, Emily;Weidlick, Jeffrey;Vilensky, Maria;Tugusheva, Marina;Felkner, Roland H;Campbell, William;Rao, Yu;Grass, David S;Buiakova, Olesia
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影响因子：
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Foucault, I;Le Bras, S;Deckert, M
通讯作者：
Deckert, M
影响因子：
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作者：
Levaot, Noam;Simoncic, Paul D.;Rottapel, Robert
通讯作者：
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