Abstract
Here we report that 5'-monophosphate (AMP)-activated protein kinase (AMPK) agonist A-769662 inhibited hydrogen peroxide (H2O2)-induced viability loss and apoptosis of human and mouse osteoblast cells. H2O2-induced moderate AMPK activation in osteoblast cells, which was enhanced by A-769662. Inactivation of AMPK by its inhibitor compound C, or by target shRNA-mediated silencing and kinase dead (KD) mutation exacerbated H2O2-induced cytotoxicity in osteoblast cells. A-769662-mediated protective effect against H2O2 was also blocked by AMPK inhibition or depletion. A-769662 inhibited reactive oxygen species (ROS) accumulation by H2O2 in osteoblast cells. Meanwhile, H2O2-induced ATP depletion was inhibited by A-769662, but was aggravated by compound C. Further, H2O2 induced AMPK-dependent and pro-survival autophagy in cultured osteoblast cells, which was enhanced by A-769662. Our results suggested that activation of AMPK by H2O2 is anti-apoptosis and pro-survival in osteoblast cells, probably due to its anti-oxidant, pro-autophagy and ATP preservation abilities, and A-769662-mediated cell-protective effect in osteoblast cells requires AMPK activation. Our study suggests that A-769662 might be further investigated as a novel anti-osteonecrosis agent.
Highlights
In the pathological condition of osteonecrosis, bones become fragile and will lead to bone fracture if not treated properly
We tested whether A-769662 affected osteoblast cell apoptosis
These results indicated that A-769662 significantly suppressed H2O2-induced osteoblast cell apoptosis
Summary
In the pathological condition of osteonecrosis, bones become fragile and will lead to bone fracture if not treated properly. Studies have shown that osteonecrosis is associated with oxidative stress in osteoblasts. Elevated reactive oxygen species (ROS) (i.e., hydrogen peroxide (H2O2)) induce osteoblasts dysfunction and apoptosis, serving as an important contributor of osteonecrosis [1,2]. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimer kinase composed of α, β and γ subunits. It is a member of metabolite-sensing kinase family, which plays important roles in metabolic balance [3,4]. Recent studies suggest that AMPK is important for cell survival under stress conditions. AMPK-dependent tuberous sclerosis complex 2 (TSC2) phosphorylation is important for cell survival under energy starvation conditions [6]. The defensive role of AMPK in H2O2-induced cell apoptosis is still debatable
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