Targeted activation of AMPK by GSK621 ameliorates H 2 O 2 -induced damages in osteoblasts

Weidong Liu; Li Mao; Feng Ji; Fengli Chen; Yuedong Hao; Gang Liu

doi:10.18632/oncotarget.14454

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Research Papers:

Targeted activation of AMPK by GSK621 ameliorates H₂O₂-induced damages in osteoblasts

Weidong Liu, Li Mao, Feng Ji, Fengli Chen _, Yuedong Hao and Gang Liu

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Oncotarget. 2017; 8:10543-10552. https://doi.org/10.18632/oncotarget.14454

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Abstract

Weidong Liu 1,*, Li Mao2,*, Feng Ji1, Fengli Chen3, Yuedong Hao1, Gang Liu1

1Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

2Department of Endocrinology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

3Clinical Laboratory, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

*Co-first authors

Correspondence to:

Feng Ji, email: [email protected]

Keywords: osteonecrosis, osteoblasts, AMPK, GSK621, oxidative stress

Received: December 01, 2016 Accepted: December 09, 2016 Published: January 02, 2017

ABSTRACT

GSK621 is a novel AMP-activated protein kinase (AMPK) activator. This study tested its potential cytoprotective effect in hydrogen peroxide (H₂O₂)-treated osteoblasts. In cultured MC3T3-E1 osteoblastic cells and primary murine osteoblasts, GSK621 significantly attenuated H₂O₂-induced cell death and apoptosis. AMPK activation was required for GSK621-induced osteoblast cytoprotection. Inhibition of AMPK, by AMPKα1 T172A mutation or shRNA silence, almost completely blocked GSK621-induced osteoblast cytoprotection. Reversely, introduction of a constitutively-active AMPKα1 (T172D) alleviated H₂O₂ injuries in MC3T3-E1 cells. Further, GSK621 increased nicotinamide adenine dinucleotide phosphate (NADPH) content in osteoblasts to inhibit H₂O₂-induced reactive oxygen species (ROS) production. Meanwhile, GSK621 activated cytoprotective autophagy in the osteoblasts. On the other hand, pharmacological inhibition of autophagy alleviated GSK621-mediated osteoblast cytoprotection against H₂O₂. These results suggest that targeted activation of AMPK by GSK621 ameliorates H₂O₂-induced osteoblast cell injuries.

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Research Papers:

Targeted activation of AMPK by GSK621 ameliorates H2O2-induced damages in osteoblasts

Abstract

Targeted activation of AMPK by GSK621 ameliorates H₂O₂-induced damages in osteoblasts