Targeted activation of AMPK by GSK621 ameliorates H2O2-induced damages in osteoblasts
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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
Feng Ji, email: [email protected]
Keywords: osteonecrosis, osteoblasts, AMPK, GSK621, oxidative stress
Received: December 01, 2016 Accepted: December 09, 2016 Published: January 02, 2017
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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