miR-107 inhibition upregulates CAB39 and activates AMPK-Nrf2 signaling to protect osteoblasts from dexamethasone-induced oxidative injury and cytotoxicity

被引:5
作者
Zhuang, Yu [1 ]
Wang, Shouguo [1 ]
Fei, Haodong [1 ]
Ji, Feng [1 ]
Sun, Peng [1 ]
机构
[1] Nanjing Med Univ, Dept Orthoped, Affiliated Huaian 1 Peoples Hosp, Huaian, Peoples R China
来源
AGING-US | 2020年 / 12卷 / 12期
关键词
miR-107; CAB39; osteoblasts; dexamethasone; AMPK-Nrf2; signaling; INDUCED APOPTOSIS; CELL-GROWTH; KINASE; AMPK; DAMAGES; INDUCTION; AUTOPHAGY; PATHWAY; STRESS; PP2A;
D O I
暂无
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
To human osteoblasts dexamethasone (DEX) treatment induces significant oxidative injury and cytotoxicity. Inhibition of CAB39 (calcium binding protein 39)-targeting microRNA can induce CAB39 upregulation, activating AMP-activated protein kinase (AMPK) signaling and offering osteoblast cytoprotection. Here we identified a novel CAB39-targeting miRNA: the microRNA-107 (miR-107). RNA-Pull down assay results demonstrated that the biotinylated-miR-107 directly binds to CAB39 mRNA in OB-6 human osteoblastic cells. Forced overexpression of miR-107, by infection of pre-miR-107 lentivirus or transfection of wild-type miR-107 mimic, largely inhibited CAB39 expression in OB-6 cells and primary human osteoblasts. Contrarily, miR-107 inhibition, by antagomiR-107, increased its expression, resulting in AMPK cascade activation. AntagomiR-107 largely attenuated DEX-induced cell death and apoptosis in OB-6 cells and human osteoblasts. Importantly, osteoblast cytoprotection by antagomiR-107 was abolished with AMPK in-activation by AMPK alpha 1 dominant negative mutation, silencing or knockout. Further studies demonstrated that antagomiR-107 activated AMPK downstream Nrf2 cascade to inhibit DEX-induced oxidative injury. Conversely, Nrf2 knockout almost abolished antagomiR-107-induced osteoblast cytoprotection against DEX. Collectively, miR-107 inhibition induced CAB39 upregulation and activated AMPK-Nrf2 signaling to protect osteoblasts from DEX-induced oxidative injury and cytotoxicity.
引用
收藏
页码:11754 / 11767
页数:14
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