Song Fangfang, Lee Won Dong, Marmo Tyler, Ji Xing, Song Chao, Liao Xueyang, Seeley Rebbeca, Yao Lutian, Liu Haoran, Long Fanxin
Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children's Hospital of Philadelphia.
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
bioRxiv. 2023 Jan 18:2023.01.16.524248. doi: 10.1101/2023.01.16.524248.
Skeletal fragility is associated with type 2 diabetes mellitus (T2D), but the underlying mechanism is not well understood. Here, in a mouse model for youth-onset T2D, we show that both trabecular and cortical bone mass are reduced due to diminished osteoblast activity. Stable isotope tracing in vivo with C-glucose demonstrates that both glycolysis and glucose fueling of the TCA cycle are impaired in diabetic bones. Similarly, Seahorse assays show suppression of both glycolysis and oxidative phosphorylation by diabetes in bone marrow mesenchymal cells as a whole, whereas single-cell RNA sequencing reveals distinct modes of metabolic dysregulation among the subpopulations. Metformin not only promotes glycolysis and osteoblast differentiation in vitro, but also improves bone mass in diabetic mice. Finally, targeted overexpression of Hif1a or Pfkfb3 in osteoblasts of T2D mice averts bone loss. The study identifies osteoblast-intrinsic defects in glucose metabolism as an underlying cause of diabetic osteopenia, which may be targeted therapeutically.
骨骼脆弱与2型糖尿病（T2D）相关，但其潜在机制尚不清楚。在此，在一个青少年发病型T2D小鼠模型中，我们发现由于成骨细胞活性降低，小梁骨和皮质骨量均减少。用¹³C-葡萄糖进行的体内稳定同位素示踪表明，糖尿病骨骼中的糖酵解和三羧酸循环的葡萄糖供能均受损。同样，海马实验表明，糖尿病会抑制整个骨髓间充质细胞中的糖酵解和氧化磷酸化，而单细胞RNA测序揭示了亚群之间不同的代谢失调模式。二甲双胍不仅在体外促进糖酵解和成骨细胞分化，还能改善糖尿病小鼠的骨量。最后，在T2D小鼠的成骨细胞中靶向过表达Hif1a或Pfkfb3可避免骨质流失。该研究确定成骨细胞内在的葡萄糖代谢缺陷是糖尿病性骨质减少的一个潜在原因，这可能成为治疗靶点。
