mTORC1 Inhibits NF-kappa B/NFATc1 Signaling and Prevents Osteoclast Precursor Differentiation, In Vitro and In Mice
mTORC1 Inhibits NF-kappa B/NFATc1 Signaling and Prevents Osteoclast Precursor Differentiation, In Vitro and In Mice
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mTORC1 在体外和小鼠体内抑制 NF-kappa B/NFATc1 信号传导并防止破骨细胞前体分化
DOI：
10.1002/jbmr.3172
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发表时间：
2017
影响因子：
6.2
通讯作者：
Bai Xiaochun
中科院分区：
文献类型：
--
作者：
Zhang Yue;Xu Song;Li Kai;Tan Kang;Liang Kangyan;Wang Jian;Shen Junhui;Zou Wenchong;Hu Le;Cai Daozhang;Ding Changhai;Li Mangmang;Xiao Guozhi;Liu Bin;Liu Anling;Bai Xiaochun
雷帕霉素复合物1（mTORC 1）的机制靶点是骨稳态和骨形成的关键传感器;然而，mTORC 1在破骨细胞发育中的作用和潜在机制尚未完全建立。在这里，我们发现mTORC 1活性下降破骨细胞前体分化在体外和体内。我们使用LyzM-cre小鼠进一步靶向缺失Raptor（mTORC 1关键成分）或Tsc 1（mTORC 1负调节因子），以组成性抑制或激活破骨细胞前体（单核细胞/巨噬细胞）中的mTORC 1。在Raptor缺陷型骨髓单核细胞/巨噬细胞（BMPs）培养物中，骨形成显著增加，Raptor缺陷型小鼠表现出骨质减少伴破骨细胞生成增强。相反，缺乏Tsc 1的BMMs在破骨细胞样分化和吸收功能方面表现出严重缺陷，但这两者在雷帕霉素治疗后都得到了恢复。重要的是，活化B细胞的核因子κ轻链增强子（NF-κB）和活化T细胞的核因子，胞质1（NFATc 1），破骨细胞分化所必需的转录因子的表达受破骨细胞谱系中mTORC 1的负调控。这些结果提供了mTORC 1作为骨细胞分化限制信号发挥关键作用的证据，并表明临床上使用mTOR抑制剂治疗骨丢失相关疾病的潜在缺点。© 2017美国骨与矿物质研究学会。
The mechanistic target of rapamycin complex 1 (mTORC1) is a critical sensor for bone homeostasis and bone formation; however, the role of mTORC1 in osteoclast development and the underlying mechanisms have not yet been fully established. Here, we found that mTORC1 activity declined during osteoclast precursors differentiation in vitro and in vivo. We further targeted deletion of Raptor (mTORC1 key component) or Tsc1 (mTORC1 negative regulator) to constitutively inhibit or activate mTORC1 in osteoclast precursors (monocytes/macrophages), usingLyzM‐cre mice. Osteoclastic formation was drastically increased in cultures of Raptor deficient bone marrow monocytes/macrophages (BMMs), and Raptor‐deficient mice displayed osteopenia with enhanced osteoclastogenesis. Conversely, BMMs lacking Tsc1 exhibited a severe defect in osteoclast‐like differentiation and absorptive function, both of which were restored following rapamycin treatment. Importantly, expression of nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), transcription factors that are essential for osteoclast differentiation was negatively regulated by mTORC1 in osteoclast lineages. These results provide evidence that mTORC1 plays as a critical role as an osteoclastic differentiation‐limiting signal and suggest a potential drawback in treating bone loss–related diseases with mTOR inhibitors clinically. © 2017 American Society for Bone and Mineral Research.