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Nature子刊:中科院生化所邹卫国研究组发现骨发育与重建及锁骨颅骨发育不全综合征的新机制

摘要 : 2017年7月7日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了中国科学院生物化学与细胞生物学研究所邹卫国研究组与上海交通大学医学院附属第九人民医院汪俊研究组合作的论文

2017年7月7日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了中国科学院生物化学与细胞生物学研究所邹卫国研究组与上海交通大学医学院附属第九人民医院汪俊研究组合作的论文“mTOR/Raptor signaling is critical for skeletogenesis in mice through the regulation of Runx2 expression”。此研究发现雷帕霉素靶蛋白mTORC1通过调节成骨细胞中Runx2的表达影响骨骼系统的发育,是骨发育与相关疾病基础研究新的重要发现。

锁骨颅骨发育不全综合征(cleidocranial dysplasia,CCD)是一种常见的先天性全身骨骼发育不全性疾病。转录因子Runx2是决定成骨细胞命运及功能发挥的重要转录因子,人类转录因子Runx2基因单倍体突变、小鼠Runx2单倍体缺失均可出现CCD表型,然而临床研究表明许多CCD患者并不存在Runx2基因的突变。在邹卫国研究员和汪俊教授的共同指导下,上海交通大学医学院附属第九人民医院博士研究生代庆刚等通过条件性敲除小鼠模型发现,成骨前体细胞mTOR及mTOR调节相关蛋白(Raptor)分别缺失导致的小鼠骨发育异常,表型与人类CCD十分相似。体内外研究表明mTORC1失活导致间充质干细胞不能有效分化为成骨细胞。进一步分子机制研究表明mTORC1可通过雌激素受体α(ERα)调控Runx2的表达,进而影响成骨细胞的分化与功能,调节骨骼系统的发育。

此研究围绕锁骨颅骨发育不全的分子机制展开,表明雷帕霉素靶蛋白复合物1(mTORC1)是成骨细胞中影响骨骼系统发育的关键因子,提示通过调节成骨细胞中mTORC1的活性,可影响成骨细胞的功能与骨骼系统的发育;也为CCD病症的发病机理提供了新的见解。

研究组同时亦关注了mTORC1在破骨细胞中的功能,研究结果于2017年1月6日发表于国际学术期刊Journal of Biological Chemistry,表明条件性失活mTORC1信号可抑制破骨细胞分化及功能,进而导致小鼠骨量上升。

以上两个研究表明mTORC1在骨发育与重建过程中均发挥着关键而又复杂的作用,提示在临床应用mTOR信号抑制时应密切关注骨骼系统的副作用,同时也为骨代谢相关疾病如锁骨颅骨发育不全综合征、骨质疏松症的治疗提供了新的思路。

原文链接:

mTOR/Raptor signaling is critical for skeletogenesis in mice through the regulation of Runx2 expression

原文摘要:

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 regulatesRunx2 expression through phosphorylation of estrogen receptor α, which binds to Distal-less homeobox 5 (DLX5) and augments the activity of Runx2enhancer. 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 vivothrough 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.

来源: Cell Death & Differentiation 浏览次数:0

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