河北医科大学学报 ›› 2020, Vol. 41 ›› Issue (10): 1130-1135.doi: 10.3969/j.issn.1007-3205.2020.10.004

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胰岛素受体底物1对成骨细胞分化的影响及机制

  

  1. 1.河北医科大学第三医院内分泌科，河北省骨科生物力学重点实验室，河北 石家庄 050051；2.河北医科大学期刊社，
    河北 石家庄 050017；3.约翰·霍普金斯医学院肌肉与骨骼研究中心，美国 马里兰 21212
  • 出版日期:2020-10-25 发布日期:2020-10-27
  • 作者简介:王娜(1989-)，女，河北石家庄人，河北医科大学第三医院医师，医学博士，从事内分泌与代谢病诊治研究。
  • 基金资助:
    河北省“三三三人才工程”培养项目（A2017003079）；京津冀基础研究合作专项（19JCZDJC65500Z）；河北省医学适用技术跟踪项目（G2019008）；骨质疏松和骨矿盐疾病中青年医生优才培养计划暨白求恩·石药骨质疏松科研基金项目（GX20191107）；河北省政府资助专科能力建设和专科带头人培养项目（361005）

The effects of IRS-1 on osteogenic differentiation and the mechanism

  1. 1.Department of Endocrinology, the Third Hospital of Hebei Medical University, Key Orthopaedic 
    Biomechanics Laboratory of Hebei Province, Shijiazhuang 050051， China； 2.Department of 
    Editorial, Hebei Medical University, Shijiazhuang 050017， China； 3.Center for 
    Musculoskeletal Research, Johns Hopkins University, the United States of 
    America, Maryland 21212，America
  • Online:2020-10-25 Published:2020-10-27

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摘要： 目的  探讨胰岛素受体底物1（insulin receptor substrate 1，IRS-1）/具有盘状同源区域结合序列的转录共活化因子（transcriptional coactivator with PDZ-binding motif，TAZ）信号通路对大鼠骨髓间充质干细胞（bone marrow derived mesenchymal stem cells，BMSCs）成骨分化的影响。
方法  动物实验部分，采用微型电脑断层成像（micro-computed tomography，μCT）比较对照组、假手术组、去卵巢手术（ovariectomy，OVX）组大鼠股骨的骨量，应用免疫荧光染色比较3组间股骨IRS-1表达差异；细胞实验部分，应用质粒转染技术干预IRS-1和TAZ的表达，采用茜素红染色和Western blot分析钙结节形成和成骨分化相关蛋白表达。
结果  OVX大鼠股骨的骨量相关指标明显减低（P＜0.05），股骨中IRS-1表达明显减少（P＜0.05）；IRS-1表达上调可以增加TAZ、结合Runt相关转录因子2（runt related transcription factor 2，RUNX2）和骨钙蛋白（osteocalcin,OCN）的表达，从而促进BMSCs向成骨细胞分化；敲除IRS-1或TAZ可以抑制BMSCs向成骨细胞分化。
结论  IRS-1可通过上调TAZ表达，促进BMSCs向成骨细胞分化，IRS-1/TAZ可作为基因修饰干细胞治疗糖尿病性骨质疏松症的新靶点。


关键词: 骨质疏松, 骨髓间充质干细胞, 胰岛素受体底物1

Abstract: Objective  To explore the influence of insulin receptor substrate 1(IRS-1)/transcriptional coactivator with PDZ-binding motif(TAZ) signaling on the osteogenic differentiation of bone marrow derived mesenchymal stem cells(BMSCs). 
Methods  In vivo, the bone mass of rat femurs in control group, sham group and ovariectomy(OVX) group was analyzed by micro-computed tomography(μCT) and the IRS-1 expression in rat femurs was analyzed by immunofluorescence assay. In vitro, the plasmid transfection was used to change the IRS-1 and TAZ expression in BMSCs, the alizarin red staining and western blot was used to analyze the calcium nodules and the expression of the osteogenic differentiation related proteins, respectively. 
Results  The bone mass and the IRS-1 expression in rat femurs was significantly reduced in OVX group. High expression of IRS-1 in BMSCs increased the expression of TAZ, runt related transcription factor 2(RUNX2) and osteocalcin(OCN) proteins, which promoted the osteogenic differentiation of BMSCs. Knockout of IRS-1 or TAZ inhibited the osteogenic differentiation of BMSCs. 
Conclusion  IRS-1 increased the TAZ expression, which promoted the osteogenic differentiation of BMSCs. IRS-1/TAZ signaling in stem cells might be a new target to treat diabetic osteoporosis. 


Key words: osteoporosis, bone marrow derived mesenchymal stem cell, insulin receptor substrate 1

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