Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice.
Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice.
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作者：
Song F;Lee WD;Marmo T;Ji X;Song C;Liao X;Seeley R;Yao L;Liu H;Long F
骨骼脆性与2型糖尿病(T2D)有关，但其潜在机制尚不清楚。这里，在青春期T2D的小鼠模型中，我们发现由于成骨细胞活性降低，骨小梁和皮质骨量均减少。~(13)C-葡萄糖在体内的稳定同位素示踪表明，糖尿病骨骼中TCA循环的糖酵解和葡萄糖补充都受到了损害。同样，海马氏试验显示糖尿病抑制了整个骨髓间充质细胞的糖酵解和氧化磷酸化，而单细胞RNA测序显示了不同亚群之间的代谢失调模式。二甲双胍不仅能促进体外糖酵解和成骨细胞分化，还能改善糖尿病小鼠的骨量。最后，成骨细胞特异性过表达HIF1a，糖酵解的一般诱导剂，或PFKFB3，刺激糖酵解的特定步骤，避免T2D小鼠的骨丢失。这项研究发现，糖代谢中的成骨细胞固有缺陷是糖尿病骨量减少的潜在原因，这可能是治疗的靶点。
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 is reduced due to diminished osteoblast activity. Stable isotope tracing in vivo with 13C-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, osteoblast-specific overexpression of either Hif1a, a general inducer of glycolysis, or Pfkfb3 which stimulates a specific step in glycolysis, averts bone loss in T2D mice. The study identifies osteoblast-intrinsic defects in glucose metabolism as an underlying cause of diabetic osteopenia, which may be targeted therapeutically.