2. Academic Validation
  3. AKT/GSK3β/NFATc1 and ROS signal axes are involved in AZD1390-mediated inhibitory effects on osteoclast and OVX-induced osteoporosis

AKT/GSK3β/NFATc1 and ROS signal axes are involved in AZD1390-mediated inhibitory effects on osteoclast and OVX-induced osteoporosis

  • Int Immunopharmacol. 2022 Dec;113(Pt A):109370. doi: 10.1016/j.intimp.2022.109370.
Shuyue Yang 1,  Dezhi Song 2,  Ziyi Wang 3,  Yuangang Su 2,  Junchun Chen 1,  Yansi Xian 1,  Jian Huang 4,  Jing Li 1,  Jiake Xu 3,  Jinmin Zhao 5,  Qian Liu 6
Affiliations

Affiliations

  • 1 Research Centre for Regenerative Medicine, Orthopaedic Department, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China; Innovation Centre of Regenerative Medicine and Medical Biological Resource Development and Application, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 2 Research Centre for Regenerative Medicine, Orthopaedic Department, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 3 School of Biomedical Sciences, the University of Western Australia, Perth, WA 6009, Australia.
  • 4 Research Centre for Regenerative Medicine, Orthopaedic Department, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
  • 5 Research Centre for Regenerative Medicine, Orthopaedic Department, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China. Electronic address: [email protected].
  • 6 Research Center of Orthopedic Regenerative Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China. Electronic address: [email protected].
PMID: 36327872 DOI: 10.1016/j.intimp.2022.109370
Abstract

As a common disease in modern society, osteoporosis is caused by osteoclast hyperactivation, leading to enhanced bone resorption. Reactive Oxygen Species (ROS) metobolism and nuclear factor-activated T cells 1 (NFATc1) activities are two crucial processes during osteoclastogenesis. AZD1390 (AZD), an inhibitor of ataxia telangiectasia mutated (ATM), has been reported for antitumor effects, but little is known about how it plays a function in metabolic bone disease. Here, we found that AZD inhibitsthe generation, function and ROS-scavenging enzyme activity of mature osteoclast induced by RANKL stimulation, in a dose-dependent manner.Mechanistic analysis shows thatAZD affects osteoclast function and differentiation by inhibiting RANKL-induced NFATc1 signaling pathway and by increasing ROS-scavenging Enzymes production in oxidative stress pathways. Preclinical studies have shown that AZD protects against bone loss in an ovariectomy (OVX) mouse model. Finally, our data confirm that AZD may prevent OVX-induced bone loss by abrogating RANKL-induced Akt/GSK3β/NFATc1 signaling pathways, and by promoting the expression of ROS scavenging Enzymes in oxidative stress pathways.Collectively, our research shows that AZD has the potential as a new therapeutic agent for osteoporosis.

Keywords

AKT/GSK3β/NFATc1 signaling; AZD1390; Osteoclasts; Osteoporosis; ROS.

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