Dexamethasone-induced mitochondrial ROS-mediated inhibition of AMPK activity facilitates osteoblast necroptosis

Abstract

Abstract Long-term or high-dose glucocorticoid use can lead to serious orthopedic complications, including femoral head necrosis. Both basic and clinical studies have shown that high doses dexamethasone (Dex) can directly induce osteoblasts death. This study investigated the mechanism underlying Dex induced osteoblast death. In this study, we showed that Dex induces osteoblast necroptosis, rather than apoptosis, through the inhibition of AMP-activated protein kinase (AMPK) activity. We also demonstrated that inactivation of AMPK-mediated necroptosis is through receptor-interacting protein kinase 3 (RIP3), but not RIP1. Furthermore, we found that Dex-induced necroptosis is dependent on mitochondrial reactive oxygen species (ROS) following with directly activation of RIP1 and inactivation of AMPK. These findings provide new insights into the mechanism of Dex-induced osteoblast death and may have implications for the development of new therapies for osteoporosis and other bone-related diseases.