CGK733 alleviates ovariectomy-induced bone loss through blocking RANKL-mediated Ca2+ oscillations and NF-κB/MAPK signaling pathways

Minglian Xu; Dezhi Song; Xiaoxiao Xie; Yiwu Qin; Jian Huang; Chaofeng Wang; Junchun Chen; Yuangang Su; Jiake Xu; Jinmin Zhao; Qian Liu

doi:10.1016/j.isci.2023.107760

CGK733 alleviates ovariectomy-induced bone loss through blocking RANKL-mediated Ca²⁺ oscillations and NF-κB/MAPK signaling pathways

iScience. 2023 Aug 29;26(10):107760. doi: 10.1016/j.isci.2023.107760. eCollection 2023 Oct 20.

Authors

Minglian Xu^{1

2}, Dezhi Song^{1

2}, Xiaoxiao Xie^{1

2}, Yiwu Qin^{1

2}, Jian Huang^{1

2}, Chaofeng Wang^{1

2}, Junchun Chen^{1

2}, Yuangang Su^{1

2}, Jiake Xu^{3

4}, Jinmin Zhao^{1

2}, Qian Liu^{1

2}

Affiliations

¹ Guangxi Key Laboratory of Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
² Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, China.
³ School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia.
⁴ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China.

Abstract

Osteoporosis is a prevalent systemic metabolic disease in modern society, in which patients often suffer from bone loss due to over-activation of osteoclasts. Currently, amelioration of bone loss through modulation of osteoclast activity is a major therapeutic strategy. Ataxia telangiectasia mutated (ATM) inhibitor CGK733 (CG) was reported to have a sensitizing impact in treating malignancies. However, its effect on osteoporosis remains unclear. In this study, we investigated the effects of CG on osteoclast differentiation and function, as well as the therapeutic effects of CG on osteoporosis. Our study found that CG inhibits osteoclast differentiation and function. We further found that CG inhibits the activation of NFATc1 and ultimately osteoclast formation by inhibiting RANKL-mediated Ca²⁺ oscillation and the NF-κB/MAPK signaling pathway. Next, we constructed an ovariectomized mouse model and demonstrated that CG improved bone loss in ovariectomized mice. Therefore, CG may be a potential drug for the prevention and treatment of osteoporosis.

Keywords: Biological sciences; Molecular biology; Molecular physiology.