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

• Published in: International immunopharmacology 2022-12, Vol.113, p.109370-109370, Article 109370
• Main Authors: Yang, Shuyue, Song, Dezhi, Wang, Ziyi, Su, Yuangang, Chen, Junchun, Xian, Yansi, Huang, Jian, Li, Jing, Xu, Jiake, Zhao, Jinmin, Liu, Qian
• Format: Article
• Language: English
• Subjects: AKT/GSK3β/NFATc1 signaling; AZD1390; Osteoclasts; Osteoporosis; ROS
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109370

[Display omitted] •Our original research demonstrated that AZD1390 inhibited osteoclastogenesis in a concentration-dependent and time-dependent manner.•The inhibition is via the AKT/GSK3β/NFATc1 pathway and the ROS pathway.•The potential value of AZD1390 in the prevention of osteoporosis was demonstrated in an OVX animal model. 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.