Aging Reduces an ERRalpha-Directed Mitochondrial Glutaminase Expression Suppressing Glutamine Anaplerosis and Osteogenic Differentiation of Mesenchymal Stem Cells
Aging Reduces an ERRalpha-Directed Mitochondrial Glutaminase Expression Suppressing Glutamine Anaplerosis and Osteogenic Differentiation of Mesenchymal Stem Cells
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衰老会减少 ERRα 引导的线粒体谷氨酰胺酶表达，从而抑制谷氨酰胺回补和间充质干细胞的成骨分化。
DOI：
10.1002/stem.2470
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发表时间：
2017-02-01
期刊：
影响因子：
5.2
通讯作者：
Guan, Min
中科院分区：
文献类型：
--
作者：
Huang, Tongling;Liu, Renzhong;Guan, Min
衰老使间充质干细胞/基质细胞（MSCs）的成骨能力恶化，导致骨重建失衡和骨质疏松症。谷氨酰胺酶（Gls）在线粒体谷氨酰胺（Gln）依赖性回补的第一步将谷氨酰胺分解代谢成谷氨酸，这对于成骨分化后的MSC是必需的。雌激素相关受体α（ERR α）调节线粒体功能所需的基因。在这里，我们发现ERRa和Gls通过人MSC（hMSC）中的成骨诱导而上调。相比之下，MSC的成骨分化能力和谷氨酰胺消耗以及ERR α、Gls和成骨标志物基因随着年龄的增长而显著降低。我们证明了ERR α与Gls启动子上的应答元件结合，并通过Gls的转录诱导影响谷氨酰胺回补。相反，mTOR抑制剂雷帕霉素、ERR α反向激动剂化合物29或Gls抑制剂BPTES导致hMSC的Gln回补减少和成骨分化恶化。重要的是，ERRa或Gls的过表达恢复了这些抑制剂的损伤。最后，我们证明了ERR α或Gls的补偿表达确实增强了老年小鼠MSCs体外的Gln回补和成骨能力。总之，我们确定Gls是一种新的ERR α靶基因，ERR α/Gls信号通路在MSC的成骨分化中起着重要作用，为新型再生疗法的开发提供了新的视角。我们的研究结果表明，恢复与年龄相关的线粒体谷氨酰胺依赖性回补可能有利于退行性骨疾病，如骨质疏松症。
Aging deteriorates osteogenic capacity of mesenchymal stem/stromal cells (MSCs), contributing to imbalanced bone remodeling and osteoporosis. Glutaminase (Gls) catabolizes glutamine into glutamate at the first step of mitochondrial glutamine (Gln)-dependent anaplerosis which is essential for MSCs upon osteogenic differentiation. Estrogen-related receptor alpha (ERR alpha) regulates genes required for mitochondrial function. Here, we found that ERR alpha and Gls are upregulated by osteogenic induction in human MSCs (hMSCs). In contrast, osteogenic differentiation capacity and glutamine consumption of MSCs, as well as ERR alpha, Gls and osteogenic marker genes are significantly reduced with age. We demonstrated that ERR alpha binds to response elements on Gls promoter and affects glutamine anaplerosis through transcriptional induction of Gls. Conversely, mTOR inhibitor rapamycin, ERR alpha inverse agonist compound 29 or Gls inhibitor BPTES leads to reduced Gln anaplerosis and deteriorated osteogenic differentiation of hMSCs. Importantly, overexpression of ERR alpha or Gls restored impairment by these inhibitors. Finally, we proved that compensated ERR alpha or Gls expression indeed potentiated Gln anaplerosis and osteogenic capability of elderly mice MSCs in vitro. Together, we establish that Gls is a novel ERR alpha target gene and ERR alpha/Gls signaling pathway plays an important role in osteogenic differentiation of MSCs, providing new sights into novel regenerative therapeutics development. Our findings suggest that restoring age-related mitochondrial Gln-dependent anaplerosis may be beneficial for degenerative bone disorders such as osteoporosis.