Corylifol A suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss via attenuating ROS production and impairing mitochondrial function

Hai Shan Li, Wei Deng, Jia Min Yang, Yue Wei Lin, Shi Yin Zhang, Zi Xuan Liang, Jun Chun Chen, Min Hua Hu, Teng Liu, Guo Ye Mo, Zhen Zhang, Dong Ping Wang, Peng Gu, Yong Chao Tang, Kai Yuan, Liang Liang Xu, Jia Ke Xu, Shun Cong Zhang, Yong Xian Li

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Abstract

Osteoporosis is a systemic disease characterized by an imbalance in bone homeostasis, where osteoblasts fail to fully compensate for the bone resorption induced by osteoclasts. Corylifol A, a flavonoid extracted from Fructus psoraleae, has been identified as a potential treatment for this condition. Predictions from network pharmacology and molecular docking studies suggest that Corylifol A exhibits strong binding affinity with NFATc1, Nrf2, PI3K, and AKT1. Empirical evidence from in vivo experiments indicates that Corylifol A significantly mitigates systemic bone loss induced by ovariectomy by suppressing both the generation and activation of osteoclasts. In vitro studies further showed that Corylifol A inhibited the activation of PI3K-AKT and MAPK pathways and calcium channels induced by RANKL in a time gradient manner, and specifically inhibited the phosphorylation of PI3K, AKT, GSK3 β, ERK, CaMKII, CaMKIV, and Calmodulin. It also diminishes ROS production through Nrf2 activation, leading to a decrease in the expression of key regulators such as NFATcl, C-Fos, Acp5, Mmp9, and CTSK that are involved in osteoclastogenesis. Notably, our RNA-seq analysis suggests that Corylifol A primarily impacts mitochondrial energy metabolism by suppressing oxidative phosphorylation. Collectively, these findings demonstrate that Corylifol A is a novel inhibitor of osteoclastogenesis, offering potential therapeutic applications for diseases associated with excessive bone resorption.

Original languageEnglish
Article number116166
Number of pages18
JournalBiomedicine and Pharmacotherapy
Volume171
Early online date19 Jan 2021
DOIs
Publication statusPublished - Feb 2024

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