IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis

IGF-1R/β-catenin信号通路在2型糖尿病性骨质疏松中的作用（英文）

Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis(DOP).Serum from patients with or without DOP was collected to measure the IGF-1 R level using enzyme-linked immunosorbent assay(ELISA).Rats were given streptozotocin following a four-week high-fat diet induction(DOP group),or received vehicle after the same period of a normal diet(control group).Dual energy X-ray absorption,a biomechanics test,and hematoxylin-eosin(HE)staining were performed to evaluate bone mass,bone strength,and histomorphology,respectively,in vertebrae.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were performed to measure the total and phosphorylation levels of IGF-1 R,glycogen synthase kinase-3β(GSK-3β),andβ-catenin.The serum IGF-1 R level was much higher in patients with DOP than in controls.DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group.HE staining showed that the histomorphology of DOP vertebrae was seriously impaired,which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae.PCR analysis demonstrated that IGF-1 R mRNA expression was significantly up-regulated,and western blotting detection showed that phosphorylation levels of IGF-1 R,GSK-3β,andβ-catenin were enhanced in DOP rat vertebrae.Our results suggest that the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of DOP.This may contribute to development of the underlying therapeutic target for DOP.

目的:探讨胰岛素样生长因子-1受体(IGF-1R)/β-联蛋白(β-catenin)信号通路是否在糖尿病性骨质疏松(DOP)病理机制中起作用。创新点:发现IGF-1R/β-catenin信号通路在DOP病理机制中起作用,可能是DOP潜在的治疗靶点。方法:收集DOP患者血清,使用酶联免疫吸附测定(ELISA)法检测IGF-1R水平。DOP大鼠在4周高脂饲料喂养后给予链脲佐菌素建模,对照组大鼠在普通饲料喂养4周后再给予链脲佐菌素溶媒(柠檬酸钠缓冲液)。应用双能X线吸收法、生物力学测试和苏木精-伊红(HE)染色法分别评估椎体骨量、骨强度和骨组织形态。使用实时定量聚合酶链反应(qRT-PCR)和蛋白印迹法(western blotting)测定IGF-1R、糖原合成酶激酶-3β(GSK-3β)和β-catenin表达及其蛋白磷酸化水平。结论:DOP患者血清IGF-1R较对照组高。DOP大鼠骨量、压缩强度明显减小,HE染色显示DOP椎体骨组织形态明显受损,IGF-1R信使RNA(mRNA)表达上调,IGF-1R、GSK-3β和β-catenin蛋白磷酸化增加。由此可见,IGF-1R/β-catenin信号通路在DOP的病理机制中起作用,该发现将有利于后期DOP治疗靶点的开发。