miR-135b expression downregulates Ppm1e to activate AMPK signaling and protect osteoblastic cells from dexamethasone

被引:58
作者
Fan, Jian-bo [1 ,4 ]
Ruan, Jian-wei [2 ]
Liu, Wei [1 ]
Zhu, Lun-qing [3 ]
Zhu, Xin-hui [1 ]
Yi, Hong [1 ]
Cui, Sheng-yu [1 ]
Zhao, Jian-ning [4 ]
Cui, Zhi-ming [1 ]
机构
[1] Nantong Univ, Affiliated Hosp 2, Dept Orthopaed, Nantong 226001, Jiangsu, Peoples R China
[2] Soochow Univ, Affiliated Hosp 2, Dept Orthoped, Suzhou 215000, Peoples R China
[3] Soochow Univ, Childrens Hosp, Ctr Diag & Treatment Childrens Bone Dis, Suzhou 215000, Jiangsu, Peoples R China
[4] Nanjing Med Univ, Jinling Hosp, Dept Orthopaed, Nanjing 210008, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
dexamethasone (Dex); osteoblastic cells; microRNA-135b; AMP-activated protein kinase (AMPK); phosphatase 1E (Ppm1e); INDUCED APOPTOSIS; CULTURED OSTEOBLASTS; KINASE PHOSPHATASE; CAMKP-N; GLUCOCORTICOIDS; STRESS; ENERGY; IDENTIFICATION; OSTEONECROSIS; HOMEOSTASIS;
D O I
10.18632/oncotarget.12138
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Activation of AMP-activated protein kinase (AMPK) could potently protect osteoblasts/osteoblastic cells from dexamethasone (Dex). We aim to induce AMPK activation via microRNA ("miRNA") downregulation of its phosphatase Ppm1e. We discovered that microRNA-135b ("miR-135b") targets the 3' untranslated regions (UTRs) of Ppm1e. In human osteoblasticOB-6 cells and hFOB1.19 cells, forced-expression of miR-135b downregulated Ppm1e and activated AMPK signaling. miR-135b also protected osteoblastic cells from Dex. shRNA-induced knockdown of Ppm1e similarly activated AMPK and inhibited Dex-induced damages. Intriguingly, in the Ppm1e-silenced osteoblastic cells, miR-135b expression failed to offer further cytoprotection against Dex. Notably, AMPK knockdown (via shRNA) or dominant negative mutation abolished miR-135b-induced AMPK activation and cytoprotection against Dex. Molecularly, miR-135b, via activating AMPK, increased nicotinamide adenine dinucleotide phosphate (NADPH) activity and inhibited Dex-induced oxidative stress. At last, we found that miR-135b level was increased in human necrotic femoral head tissues, which was correlated with Ppm1e downregulation and AMPK activation. There results suggest that miR-135b expression downregulates Ppm1e to activate AMPK signaling, which protects osteoblastic cells from Dex.
引用
收藏
页码:70613 / 70622
页数:10
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