M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase
M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase
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DOI：
10.1038/sj.cdd.4401285
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发表时间：
2003-10-01
影响因子：
12.4
通讯作者：
Reszka, AA
中科院分区：
文献类型：
--
作者：
Glantschnig, H;Fisher, JE;Reszka, AA
多核骨吸收破骨细胞（Ocl）是造血来源的细胞，在骨质疏松症病理生理学中发挥重要作用。 Ocl 的存活和活性需要 M-CSF 和 RANK 配体 (RANKL)。 M-CSF 向 Akt 发出信号，而 RANKL 与 TNFalpha 一样，激活 NF-kappaB。我们在这里表明，尽管这些是 Ocl 中的独立途径，但所有三种细胞因子的信号传导均集中在哺乳动物雷帕霉素靶标 (mTOR) 上，作为其抗凋亡作用的一部分。因此，雷帕霉素阻断 M-CSF 和 RANKL 依赖性 Ocl 存活诱导细胞凋亡，并抑制与 Ocl 数量减少成比例的体外骨吸收。 mTOR/核糖体蛋白 S6 激酶 (S6K) 激活的细胞因子信号转导中间体包括磷脂酰肌醇-3 激酶、Akt、Erks 和香叶基香叶基化蛋白。这些中间体的抑制剂抑制 S6K 的细胞因子激活并诱导 Ocl 凋亡。 mTOR 通过 S6K、4E-BP1 和 S6 调节蛋白质翻译。我们发现其他机制抑制翻译也会诱导 Ocl 凋亡，这表明 Ocl 存活对持续的从头蛋白质合成高度敏感。因此，这项研究确定 mTOR/S6K 是参与刺激破骨细胞存活的重要信号通路。
Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFalpha, activates NF-kappaB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin ( mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF- and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.