mTOR/Raptor signaling is critical for skeletogenesis in mice through the regulation of Runx2 expression.
mTOR/Raptor signaling is critical for skeletogenesis in mice through the regulation of Runx2 expression.
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mTOR/Raptor 信号传导通过调节 Runx2 表达对小鼠骨骼形成至关重要。
DOI：
10.1038/cdd.2017.110
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发表时间：
2017-11
影响因子：
12.4
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Dai Q;Xu Z;Ma X;Niu N;Zhou S;Xie F;Jiang L;Wang J;Zou W
哺乳动物雷帕霉素靶蛋白（mTOR）/mTOR调节相关蛋白（Raptor）通路传递和整合包括生长因子、营养素和能量代谢的不同信号。几乎所有这些信号都被发现在骨骼生物学中发挥作用。然而，mTOR/Raptor对体内成骨细胞生物学的贡献仍有待阐明，因为最近的研究结论存在争议。在这里，我们报告说，在前成骨细胞中缺乏mTOR或Raptor的小鼠表现出锁骨发育不全和延迟的囟门融合，类似于在人类患者中发现的锁骨颅骨发育不良（CCD）单倍不足的转录因子runt-related转录因子2（Runx 2）或Runx 2 +/−小鼠中发现的情况。机制分析显示mTOR-Raptor-S6 K1轴通过雌激素受体α的磷酸化调节Runx 2的表达，雌激素受体α与远端同源框5（DLX 5）结合并增强Runx 2增强子的活性。此外，成骨细胞中raptor的杂合突变加剧了Runx 2 +/−小鼠中观察到的骨缺损，表明Raptor和Runx 2之间存在遗传相互作用。总的来说，这些发现揭示了mTOR/Raptor信号传导通过调节Runx 2表达对于体内骨形成是必需的。这些结果还表明，已开发用于治疗许多疾病的选择性mTOR/Raptor拮抗剂可能具有引起骨丢失的副作用。
The mammalian target of rapamycin (mTOR)/regulatory-associated protein of mTOR (Raptor) pathway transmits and integrates different signals including growth factors, nutrients, and energy metabolism. Nearly all these signals have been found to play roles in skeletal biology. However, the contribution of mTOR/Raptor to osteoblast biology in vivo remains to be elucidated as the conclusions of recent studies are controversial. Here we report that mice with a deficiency of either mTOR or Raptor in preosteoblasts exhibited clavicular hypoplasia and delayed fontanelle fusion, similar to those found in human patients with cleidocranial dysplasia (CCD) haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2) or those identified in Runx2+/− mice. Mechanistic analysis revealed that the mTOR-Raptor-S6K1 axis regulates Runx2 expression through phosphorylation of estrogen receptor α, which binds to Distal-less homeobox 5 (DLX5) and augments the activity of Runx2 enhancer. Moreover, heterozygous mutation of raptor in osteoblasts aggravates the bone defects observed in Runx2+/− mice, indicating a genetic interaction between Raptor and Runx2. Collectively, these findings reveal that mTOR/Raptor signaling is essential for bone formation in vivo through the regulation of Runx2 expression. These results also suggest that a selective mTOR/Raptor antagonist, which has been developed for treatment of many diseases, may have the side effect of causing bone loss.
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