SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss.
SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss.
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SH3BP2天使突变通过NFATC1和TNF-α介导的炎症性骨质流失增强了TNF-α诱导的破骨细胞生成。
DOI：
10.1002/jbmr.2295
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发表时间：
2014-12
影响因子：
6.2
通讯作者：
Ueki, Yasuyoshi
中科院分区：
文献类型：
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作者：
Mukai, Tomoyuki;Ishida, Shu;Ishikawa, Remi;Yoshitaka, Teruhito;Kittaka, Mizuho;Gallant, Richard;Lin, Yi-Ling;Rottapel, Robert;Brotto, Marco;Reichenberger, Ernst J.;Ueki, Yasuyoshi
切尔鲁比症(OMIM#118400)是一种遗传性疾病，由信号适配器蛋白SH3BP2突变引起的颌骨过度吸收。对携带P416R敲入突变的小鼠大猩猩模型的研究表明，突变体SH3BP2增强了髓系细胞中肿瘤坏死因子-α的产生和RANKL诱导的破骨细胞分化。肿瘤坏死因子-α在人类胚胎症皮损中表达，含有大量TRAP阳性的多核细胞，在纯合胚胎症小鼠(Sh3bp2KI/KI)的炎症性骨破坏中起关键作用。这些数据提示突变型SH3BP2与肿瘤坏死因子-α介导的破骨细胞骨丢失之间存在病理生理学关系。因此，我们研究了P416R突变体SH3BP2是否参与了肿瘤坏死因子-α介导的破骨细胞形成和骨丢失。在这里，我们展示了来自杂合的大猩猩突变体(Sh3bp2KI/+)小鼠的骨髓来源的M-CSF依赖的巨噬细胞(BMM)对肿瘤坏死因子-α具有高度的响应，并可以在体外分化为不依赖RANKL的破骨细胞，其机制涉及SYK和PLCγ2的磷酸化，导致NFATc1核转位增加。在小鼠颅骨肿瘤坏死因子-α注射模型和人肿瘤坏死因子-α转基因小鼠模型(HTNFtg)中，杂合性小鼠突变加剧了破骨细胞形成，从而加剧了骨丢失。RAW264.7细胞中SH3BP2基因敲除导致TRAP阳性多核细胞形成减少。这些结果表明，SH3BP2基因突变可以通过促进破骨细胞的形成而导致颌骨的破坏，并且SH3BP2是肿瘤坏死因子-α诱导破骨细胞生成的关键调节因子。抑制破骨细胞前体细胞SH3BP2的表达可能成为治疗骨质疏松症和其他炎症性骨病的潜在策略。
Cherubism (OMIM#118400) is a genetic disorder with excessive jawbone resorption caused by mutations in the signaling adaptor protein SH3BP2. Studies on the mouse model for cherubism carrying a P416R knock-in mutation have revealed that mutant SH3BP2 enhances TNF-α production and RANKL-induced osteoclast differentiation in myeloid cells. TNF-α is expressed in human cherubism lesions, which contain a large number of TRAP-positive multinucleated cells, and TNF-α plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2KI/KI). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-α-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-α-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2KI/+) mice are highly responsive to TNF-α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves SYK and PLCγ2 phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-α injection model as well as in a human TNF-α transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-α expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF-α-induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in cherubism as well as in other inflammatory bone disorders.
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影响因子：
--
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
通讯作者：
Buiakova, Olesia
影响因子：
4
作者：
Faccio, R;Zou, W;Ross, FP
通讯作者：
Ross, FP
影响因子：
3.7
作者：
Chihara, Kazuyasu;Kimura, Yukihiro;Sada, Kiyonao
通讯作者：
Sada, Kiyonao
影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
影响因子：
15.3
作者：
Kim, N;Kadono, Y;Choi, Y
通讯作者：
Choi, Y