Idebenone attenuates RANKL-induced osteoclastogenesis and improves bone mass in ovariectomized mice

Chenxin Yu; Luqiong Cai; Luyao Zhuang; Yinuo Wu; Qihang Wu; Haibo Liang; Miaomiao Shi; Jiansen Miao; Hongpu Song; Haiming Jin; Youjin Pan

doi:10.1016/j.freeradbiomed.2025.06.043

Idebenone attenuates RANKL-induced osteoclastogenesis and improves bone mass in ovariectomized mice

Free Radic Biol Med. 2025 Jun 25:S0891-5849(25)00792-0. doi: 10.1016/j.freeradbiomed.2025.06.043. Online ahead of print.

Authors

Chenxin Yu¹, Luqiong Cai¹, Luyao Zhuang², Yinuo Wu², Qihang Wu³, Haibo Liang³, Miaomiao Shi¹, Jiansen Miao³, Hongpu Song⁴, Haiming Jin⁵, Youjin Pan⁶

Affiliations

¹ Department of Endocrinology, the 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; The 2nd School of Medicine, Wenzhou Medical University, Wenzhou, China.
² The 2nd School of Medicine, Wenzhou Medical University, Wenzhou, China.
³ The 2nd School of Medicine, Wenzhou Medical University, Wenzhou, China; Department of Orthopaedics, the 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Department of orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, China. Electronic address: shp1995@126.com.
⁵ The 2nd School of Medicine, Wenzhou Medical University, Wenzhou, China; Department of Orthopaedics, the 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: kkjinhaiming@126.com.
⁶ Department of Endocrinology, the 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; The 2nd School of Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: panyj6190@163.com.

PMID: 40578539
DOI: 10.1016/j.freeradbiomed.2025.06.043

Abstract

Postmenopausal osteoporosis (PMOP), driven by estrogen deficiency-induced osteoclast overactivation, poses a significant global health burden with limited therapeutic options. In this study, we investigated the potential of Idebenone (IDB) as a therapeutic agent for PMOP, focusing on its effects on osteoclast differentiation and underlying molecular mechanisms. Bone marrow-derived macrophages (BMMs) were cultured and stimulated to induce osteoclast differentiation, with or without IDB treatment. IDB's effects on osteoclast formation were assessed via TRAcP staining, F-actin ring visualization, resorption pit assays, and Western blotting. Network pharmacology highlighted the protein kinase B (AKT) as a key target, corroborated by molecular docking and CETSA showing IDB-AKT interaction. We found that IDB suppressed osteoclast differentiation and activity through reducing oxidative stress and inhibiting the AKT and mitogen-activated protein kinase (MAPK) signaling pathways. In vivo, ovariectomized (OVX) mice were treated with IDB (50 mg/kg) for six weeks, followed by micro-CT and histomorphometric analysis to evaluate bone microstructure and osteoclast activity. Notably, in OVX mice, IDB treatment significantly improved bone mass compared to controls. These findings suggested that IDB may serve as a promising therapeutic candidate for the treatment of postmenopausal osteoporosis by modulating osteoclast differentiation and inhibiting AKT pathways.

Keywords: Idebenone; Osteoclast; Osteoporosis; RANKL; oxidative stress.