Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis

Yuqi Guo, Chengzhi Xie, Xiyan Li, Jian Yang, Tao Yu, Ruohan Zhang, Tianqing Zhang, Deepak Saxena, Michael Snyder, Yingjie Wu and Xin Li ()
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Yuqi Guo: New York University College of Dentistry
Chengzhi Xie: New York University College of Dentistry
Xiyan Li: Stanford University
Jian Yang: New York University College of Dentistry
Tao Yu: New York University College of Dentistry
Ruohan Zhang: New York University College of Dentistry
Tianqing Zhang: New York University College of Dentistry
Deepak Saxena: New York University College of Dentistry
Michael Snyder: Stanford University
Yingjie Wu: Institute for Genomic Engineered Animal Models of Human Diseases
Xin Li: New York University College of Dentistry

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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 osteoclastogenesis in vitro and in 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.

Date: 2017
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DOI: 10.1038/ncomms15621

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