雌二醇介导SIRT1-FOXO3a对成骨细胞自噬的作用和机制研究
The effect and mechanism of estradiol mediated SIRT1-FOXO3a on autophagy in osteoblasts
  
DOI:10.3969/j.issn.1006-7108.2020.12.013
中文关键词:  17β-雌二醇  沉默信息调节因子1  5'-单磷酸腺苷活化蛋白激酶  FOXO3基因编码的人类蛋白质  线粒体自噬
英文关键词:17β-E2  SIRT1  AMPK  FOXO 3a  mitochondrial autophagy
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作者单位
唐烨* 蒋林 蒋成明 王惟达 周乾 长沙市一医院脊柱外科,湖南 长沙 410005 
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中文摘要:
      目的 探讨雌激素是否能通过增强SIRTl的活性进而对成骨细胞及其通路产生作用。方法 17β-雌二醇(17β-E2)作用于hFOB1.19成骨细胞24 h,应用荧光自噬检测试剂盒(MDC)检测成骨细胞自噬情况;应用蛋白免疫印迹技术检测自噬相关蛋白LC3的表达含量;应用蛋白免疫印迹技术检测AMPK、磷酸化的AMPK、SIRTl蛋白活性的影响;在17β-E2环境中,增强或抑制SIRTl的活性,通过电镜、激光共聚焦显微镜、流式细胞仪观察细胞形态和关键蛋白质的改变;应用免疫印迹技术及实时定量PCR检测17β-E2/SIRT1/AMPK/FOXO3a对细胞自噬相关蛋白BCL-2、Bnip3、mTOR及凋亡相关蛋白caspase-3的影响。结果 17β-E2(10-8 mmol/L,10-6 mmol/L)增加成骨细胞的自噬,成骨细胞内LC3II蛋白活性增加;随着17β-E2浓度的增加,SIRTl蛋白表达量增加,且活性增强;17β-E2增加磷酸化AMPK的水平,且AMPK可以增加成骨细胞内SIRTl的活性;SIRTl激动剂SRT1720及抑制剂Ex527可以干预17β-E2/SIRTl对成骨细胞细胞凋亡的负调节作用;应用激光共聚焦显微镜和透视电镜观察成骨细胞内17β-E2/SIRTl调节LC3蛋白,并发现SRT1720可增强成骨细胞内的双层膜结构的线粒体自噬小体的数量;介导SIRTl蛋白,17β-E2可以增加自噬相关蛋白Bcl-2和Bnip3的表达,减低mTOR的活性,增加FOXO3a活性。结论 SIRT1在17β-E2介导的成骨细胞自噬作用中起到关键作用;17β-E2可能通过AMPK/SIRT1/FOXO3a/mTOR通路介导成骨细胞自噬。
英文摘要:
      Objective To investigate whether estrogen can enhance the activity of Sirtl and then have an effect on osteoblasts and their pathways. Methods Different concentrations of 17β-E2 were applied to hFOB 1.19 after 24 hours, the autophagy of osteoblasts was detected by fluorescence autophagy detection kit (MDC); The expression of autophagy related protein LC3 was detected by Western blotting; The effect of AMPK, phosphorylated AMPK and SIRT1 on egg white activity was detected by Western blotting; SIRT1 was enhanced or inhibited in 17β-E2 environment. The changes of cell morphology and key proteins were observed by electron microscopy, confocal laser microscopy and flow cytometry; The effects of 17β-E2/SIRT1/AMPK/FOXO3a on autophagy related proteins Bcl-2, BNIP3, mTOR and caspase-3 were detected by immunoblotting and real-time quantitative PCR. Results 17β-E2 (10-8 mmol/L, 10-6 mmol/L) increased the autophagy of osteoblasts and the activity of lc3ii protein in osteoblasts; With the increase of 17β-E2 concentration, the expression of SIRT1 protein increased and the activity increased; 17β-E2 increased the level of phosphorylated AMPK, and AMPK increased the activity of SIRT1 in osteoblasts; SRT1720, SIRT1 agonist, and ex527, an inhibitor of SIRT1 It could interfere with the negative regulation of 17β-E2/SIRT1 on the apoptosis of osteoblasts; Using laser confocal microscopy and perspective electron microscopy to observe the LC3 protein regulated by 17β-E2/SIRT1 in osteoblasts, SRT1720 was found It could enhance the autophagy mediated by 17β-E2, increase the autophagy bodies in cells, and increase the mitochondrial autophagy bodies with double membrane structure; It could mediate SIRT1 protein, 17β-E2 could increase the expression of autophagy related proteins Bcl-2 and BNIP3, reduce the activity of mTOR and increase the activity of FOXO3a. Conclusion SIRT1 plays a key role in 17β-E2 mediated autophagy of osteoblasts; 17β-E2 may mediate autophagy of osteoblasts through AMPK/SIRT1/FOXO3a/mTOR pathway.
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