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

Yingchao Shen; Bo Jiang; Wei Lu; Bin Luo; Yuan Zhou; Guiying Qian

doi:10.1093/toxres/tfad080

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

Toxicol Res (Camb). 2023 Sep 23;12(5):922-929. doi: 10.1093/toxres/tfad080. eCollection 2023 Oct.

Authors

Yingchao Shen¹, Bo Jiang², Wei Lu¹, Bin Luo¹, Yuan Zhou¹, Guiying Qian¹

Affiliations

¹ Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, No. 6, Huanghe Road, Changshu, Jiangsu 215500, China.
² Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, Jiangsu 215004, China.

PMID: 37915480
PMCID: PMC10615823 (available on 2024-09-23)
DOI: 10.1093/toxres/tfad080

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.

Keywords: AMPK; dexamethasone; mitochondrial ROS; necroptosis; osteoblasts death.