Rendina-Ruedy E, Graef J L, Lightfoot S A, Ritchey J W, Clarke S L, Lucas E A, Smith B J
Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, United States.
Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
Bone Rep. 2016 Aug 8;5:199-207. doi: 10.1016/j.bonr.2016.08.001. eCollection 2016 Dec.
Patients with type 2 diabetes mellitus (T2DM) experience a 1.5-3.5 fold increase in fracture risk, but the mechanisms responsible for these alterations in bone biomechanical properties remain elusive. Macroautophagy, often referred to as autophagy, is regulated by signaling downstream of the insulin receptor. Metabolic changes associated with the progression of glucose intolerance have been shown to alter autophagy in various tissues, but limited information is available in relation to bone cells. The aim of this study was to (a) investigate whether autophagy is altered in bone tissue during impaired glucose tolerance, and (b) determine how autophagy impacts osteoblast differentiation, activity, and maturation. Four-week-old, male C57BL/6 mice were fed a control (Con) or high fat (HF) diet for 2, 8, or 16 wks. Mice on the HF diet demonstrated elevated fasting blood glucose and impaired glucose tolerance. Reduced trabecular bone in the femoral neck was evident in the mice on the HF diet by 8 wks compared to Con mice. Histological evaluation of the tibia suggested that the high fat diet promoted terminal differentiation of the osteoblast to an osteocyte. This shift of the osteoblasts towards a non-mineralizing, osteocyte phenotype appears to be coordinated by Beclin1-mediated autophagy. Consistent with these changes in the osteoblast , the induction of autophagy was able to direct MC3T3-E1 cells towards a more mature osteoblast phenotype. Although these data are somewhat observational, further investigation is warranted to determine if Beclin1-mediated autophagy is essential for the terminal differentiation of the osteoblasts and whether autophagy is having a protective or deleterious effect on bone in T2DM.
2型糖尿病（T2DM）患者的骨折风险增加1.5至3.5倍，但其骨生物力学特性发生这些改变的机制仍不清楚。巨自噬，通常称为自噬，受胰岛素受体下游信号调节。与葡萄糖耐量异常进展相关的代谢变化已被证明会改变各种组织中的自噬，但关于骨细胞的信息有限。本研究的目的是：（a）研究在葡萄糖耐量受损期间骨组织中的自噬是否发生改变；（b）确定自噬如何影响成骨细胞的分化、活性和成熟。给四周龄雄性C57BL/6小鼠喂食对照（Con）或高脂（HF）饮食2、8或16周。食用HF饮食的小鼠空腹血糖升高，葡萄糖耐量受损。与Con小鼠相比，食用HF饮食的小鼠在8周时股骨颈的小梁骨减少明显。胫骨的组织学评估表明，高脂饮食促进了成骨细胞向骨细胞的终末分化。成骨细胞向非矿化骨细胞表型的这种转变似乎是由Beclin1介导的自噬协调的。与成骨细胞的这些变化一致，自噬的诱导能够引导MC3T3-E1细胞向更成熟的成骨细胞表型分化。尽管这些数据有些是观察性的，但仍有必要进一步研究以确定Beclin1介导的自噬对于成骨细胞的终末分化是否至关重要，以及自噬在T2DM中对骨是具有保护作用还是有害作用。
