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

GSK621 is a novel AMP-activated protein kinase (AMPK) activator. This study tested its potential cytoprotective effect in hydrogen peroxide (H(2)O(2))-treated osteoblasts. In cultured MC3T3-E1 osteoblastic cells and primary murine osteoblasts, GSK621 significantly attenuated H(2)O(2)-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 H(2)O(2) injuries in MC3T3-E1 cells. Further, GSK621 increased nicotinamide adenine dinucleotide phosphate (NADPH) content in osteoblasts to inhibit H(2)O(2)-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 H(2)O(2). These results suggest that targeted activation of AMPK by GSK621 ameliorates H(2)O(2)-induced osteoblast cell injuries.