DEPTOR regulates osteogenic differentiation via inhibiting MEG3-mediated activation of BMP4 signaling and is involved in osteoporosis.
DEPTOR regulates osteogenic differentiation via inhibiting MEG3-mediated activation of BMP4 signaling and is involved in osteoporosis.
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DEPTOR 通过抑制 MEG3 介导的 BMP4 信号激活来调节成骨分化，并参与骨质疏松
DOI：
10.1186/s13287-018-0935-9
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发表时间：
2018-07-04
影响因子：
7.5
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Chen S;Jia L;Zhang S;Zheng Y;Zhou Y
研究背景哺乳动物雷帕霉素靶蛋白（mTOR）通路在成骨分化和骨维持中起重要作用。作为目前已知的唯一一种内源性mTOR功能抑制剂，DEPTOR可能参与干细胞分化，但其病理生理意义及其分子机制尚不清楚。本研究旨在阐明DEPTOR对骨质疏松症进展的影响，并探讨成骨调控的潜在分子机制。MethodsAn ovariectomy mouse model with decreased bone formation and osteogenic induction with bone marrow mesenchymal stem cells（BMSCs）被用于研究DEPTOR和成骨事件之间的关系。然后进行功能丧失调查，以探讨DEPTOR在体外和体内BMSCs成骨分化中的作用。最后，长链非编码RNA（lncRNA）和mRNA序列进行了研究，以揭示成骨调控的DEPTOR的潜在机制。RNA干扰，蛋白质印迹，染色质免疫沉淀试验进行进一步的mechanistic determination.ResultsThe结果表明，DEPTOR有助于骨质疏松症的进展，和较高的表达Deptor观察骨质疏松症的骨。DEPTOR在BMSCs向成骨细胞分化过程中表达降低，在体内外敲低DEPTOR可促进BMSCs向成骨细胞分化。lncRNA和mRNA序列表明，DEPTOR的敲低上调母源表达3（非蛋白编码）（MEG 3）的表达，随后激活骨形态发生蛋白4（BMP 4）信号。此外，DEPTOR可以与特定区域结合，（-1000 bp ~ 0）的MEG 3启动子调控其转录，抑制MEG 3可降低DEPTOR敲低引发的BMP 4活化。这表明DEPTOR可能成为骨丢失疾病和骨骼组织再生的治疗靶点。
BackgroundThe mammalian target of rapamycin (mTOR) pathway plays a significant role in osteogenic differentiation and bone maintenance. As the only known endogenous inhibitor of mTOR function, DEP domain containing mTOR interacting protein (DEPTOR) is potentially involved in stem cell differentiation, although the pathophysiological significance and its molecular mechanisms remain unclear. The present study aimed to elucidate the effects of DEPTOR on the progress of osteoporosis and investigate the underlying molecular mechanisms of osteogenic regulation.MethodsAn ovariectomy mouse model with decreased bone formation and osteogenic induction with bone marrow mesenchymal stem cells (BMSCs) were used to investigate the relationship between DEPTOR and osteogenic events. A loss-of-function investigation was then performed to explore the role of DEPTOR in the osteogenic differentiation of BMSCs both in vitro and in vivo. Finally, long noncoding RNA (lncRNA) and mRNA sequences were investigated to reveal the underlying mechanisms of DEPTOR in osteogenic regulation. RNA interference, western blotting, and chromatin immunoprecipitation assays were performed for further mechanistic determination.ResultsThe results indicated that DEPTOR contributes to the progress of osteoporosis, and higher expression of Deptor was observed in osteoporotic bones. The expression of DEPTOR was reduced during the osteogenic differentiation of BMSCs, and knockdown ofDEPTORpromoted BMSC osteogenesis in vitro and in vivo. lncRNA and mRNA sequences indicated that knockdown ofDEPTORupregulated the expression of maternally expressed 3 (nonprotein coding) (MEG3), which subsequently activated bone morphogenetic protein 4 (BMP4) signaling. Furthermore, DEPTOR could bind to a specific region (− 1000 bp ~ 0) of theMEG3promoter to regulate its transcription, and inhibition ofMEG3reduced BMP4 activation triggered byDEPTORknockdown.ConclusionsTaken together, our study revealed a novel function of DEPTOR in osteogenic differentiation by inhibiting MEG3-mediated activation of BMP4 signaling, which suggested that DEPTOR could be a therapeutic target for bone loss diseases and skeletal tissue regeneration.
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影响因子：
5.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Chen, Jianquan;Holguin, Nilsson;Shi, Yu;Silva, Matthew J.;Long, Fanxin
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自噬维持骨髓间充质干细胞的功能，预防雌激素缺乏引起的骨质疏松症
影响因子：
12.4
作者：
Qi M;Zhang L;Ma Y;Shuai Y;Li L;Luo K;Liu W;Jin Y
通讯作者：
Jin Y