Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice
Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice
复制标题
破骨细胞中 mTOR (Raptor)/哺乳动物雷帕霉素靶标复合物 1 (mTORC1) 信号调节相关蛋白的失活通过抑制小鼠破骨细胞分化来增加骨量
DOI：
10.1074/jbc.m116.764761
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发表时间：
2017-01-06
影响因子：
4.8
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Dai, Qinggang;Xie, Furong;Wang, Jun
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）参与成骨细胞和软骨细胞的合成代谢，但mTORC 1在体内破骨细胞生物学中的作用仍有待阐明。在这项研究中，我们发现，在破骨细胞中mTOR（Raptor）的调节相关蛋白的缺失导致骨量增加，骨吸收减少。Raptor缺陷型骨髓源性巨噬细胞表现出较低的mTORC 1-S6 K1信号传导和延迟的破骨细胞分化，如破骨细胞数量、抗酒石酸酸性磷酸酶活性和破骨细胞特异性基因表达所确定。组成性活性S6 K1的强制表达挽救了Raptor缺陷骨髓源性巨噬细胞中受损的破骨细胞分化。此外，雷帕霉素对mTORC 1信号的药理学抑制也可以抑制破骨细胞分化和破骨细胞特异性基因表达。总之，我们的研究结果表明，mTORC 1在破骨细胞的分解代谢骨吸收网络中起着关键作用，并可能作为一个潜在的药理学靶点，用于调节骨代谢疾病中的破骨细胞活性。
Mammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptor-deficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes. Enforced expression of constitutively active S6K1 rescued the impaired osteoclast differentiation in Raptor-deficient bone marrow-derived macrophages. Furthermore, pharmacological inhibition of mTORC1 signaling by rapamycin could also inhibit osteoclast differentiation and osteoclast-specific gene expression. Taken together, our findings demonstrate that mTORC1 plays a key role in the network of catabolic bone resorption in osteoclasts and may serve as a potential pharmacological target for the regulation of osteoclast activity in bone metabolic disorders.