Oncotarget

Research Papers:

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

Jian-Bo Fan, Jian-Wei Ruan, Wei Liu, Lun-Qing Zhu, Xin-Hui Zhu, Hong Yi, Sheng-Yu Cui, Jian-Ning Zhao and Zhi-Ming Cui _

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Oncotarget. 2016; 7:70613-70622. https://doi.org/10.18632/oncotarget.12138

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Abstract

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

Correspondence to:

Zhi-Ming Cui, email: zhimingcuiorth@163.com

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

ABSTRACT

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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