miR-135b expression downregulates Ppm1e to activate AMPK signaling and protect osteoblastic cells from dexamethasone
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Jian-Bo Fan1,4,*, Jian-Wei Ruan2,*, Wei Liu1,*, Lun-Qing Zhu3, Xin-Hui Zhu1, Hong Yi1, Sheng-Yu Cui1, Jian-Ning Zhao4, Zhi-Ming Cui1
1The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
2The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China
3The Center of Diagnosis and Treatment for Childrens’ Bone Disease, Childrens’ Hospital Affiliated to Soochow University, Suzhou 215000, Jiangsu, PR China
4Department of Orthopaedics, Jinling Hospital, Nanjing Medical University, Nanjing 210008, Jiangsu, PR China
*These authors have contributed equally to this work
Zhi-Ming Cui, email: [email protected]
Keywords: dexamethasone (Dex), osteoblastic cells, microRNA-135b, AMP-activated protein kinase (AMPK), phosphatase 1E (Ppm1e)
Received: July 07, 2016 Accepted: September 06, 2016 Published: September 20, 2016
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.
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