Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis.
Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis.
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琥珀酸及其 G 蛋白偶联受体刺激破骨细胞生成
DOI：
10.1038/ncomms15621
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发表时间：
2017-05-31
影响因子：
16.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Guo Y;Xie C;Li X;Yang J;Yu T;Zhang R;Zhang T;Saxena D;Snyder M;Wu Y;Li X
糖尿病是一种以慢性高脂血症和代谢失调为特征的代谢性疾病，其骨损害的机制尚不清楚。在这里，我们展示了来自高血糖（2型糖尿病，T2 D）和血糖正常小鼠的骨髓基质细胞（BMSC）代谢组学的差异。在T2D小鼠的BMSC中，有142种代谢物受到实质性调节，其中三羧酸（TCA）循环是高脂血症损害的主要代谢途径之一。重要的是，琥珀酸是TCA循环中的中间代谢物，在T2D小鼠的BMSC中增加了24倍。琥珀酸作为一种细胞外配体，通过与破骨细胞系细胞上的特异性受体结合，在体外和体内刺激破骨细胞的生成。靶向受体激活的策略抑制破骨细胞生成。这项研究揭示了代谢物介导的破骨细胞生成调节机制，有助于代谢紊乱中的骨失调。
The mechanism underlying bone impairment in patients with diabetes mellitus, a metabolic disorder characterized by chronic hyperglycaemia and dysregulation in metabolism, is unclear. Here we show the difference in the metabolomics of bone marrow stromal cells (BMSCs) derived from hyperglycaemic (type 2 diabetes mellitus, T2D) and normoglycaemic mice. One hundred and forty-two metabolites are substantially regulated in BMSCs from T2D mice, with the tricarboxylic acid (TCA) cycle being one of the primary metabolic pathways impaired by hyperglycaemia. Importantly, succinate, an intermediate metabolite in the TCA cycle, is increased by 24-fold in BMSCs from T2D mice. Succinate functions as an extracellular ligand through binding to its specific receptor on osteoclastic lineage cells and stimulates osteoclastogenesisin vitroandin vivo. Strategies targeting the receptor activation inhibit osteoclastogenesis. This study reveals a metabolite-mediated mechanism of osteoclastogenesis modulation that contributes to bone dysregulation in metabolic disorders.