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作者

Wei Zhang An-zhu Wang Xiang Li Meng-jiao Kang Qian Liu Jing-ru Tian Xiang-yan Li Ze-yu Wang Jin-yue Zhao Jia-xing Fan Shan Wang Li-hua Qin Xiao-lin Tong Lin-hua Zhao

作者单位

¹⁴Department of Endocrinology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China ⁴Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education ²School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China ⁸Northeast Asia Research Institute of Traditional Chinese Medicine, Ministry of Education, Changchun University of Chinese Medicine, Changchun, China ¹¹School and Hospital of Stomatology, Jinzhou Medical University, Jinzhou, China ¹Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China ¹³National Center for Integrative Medicine, China-Japan Friendship Hospital, Beijing, China Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China ³These authors contributed equally: Wei Zhang, An-zhu Wang, Xiang Li, Meng-jiao Kang, Qian Liu. ⁹Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun, China ⁶The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China ¹⁰The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China ¹²Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China ⁷State Key Laboratory of Oral& Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, China ⁵Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

刊名

Phytomedicine

年份

2026

卷号

Vol.161

页码

158706

ISSN

0944-7113

关键词

Postmenopausal osteoporosis Osteoclast differentiation (+)-Magnoflorine CCDC88A WNT/β-catenin signaling Ovariectomy model

摘要

Background Postmenopausal osteoporosis is primarily driven by estrogen deficiency-associated osteoclast hyperactivation, resulting in excessive bone resorption and progressive deterioration of bone microarchitecture. Although current anti-resorptive therapies are clinically effective, their long-term application remains limited by adverse effects. Purpose This study aimed to evaluate the anti-osteoporotic effects of Gengnianshou Formula , identify its pharmacologically relevant absorbed constitu...更多

Background Postmenopausal osteoporosis is primarily driven by estrogen deficiency-associated osteoclast hyperactivation, resulting in excessive bone resorption and progressive deterioration of bone microarchitecture. Although current anti-resorptive therapies are clinically effective, their long-term application remains limited by adverse effects. Purpose This study aimed to evaluate the anti-osteoporotic effects of Gengnianshou Formula , identify its pharmacologically relevant absorbed constituents, and investigate the molecular mechanisms underlying its regulation of osteoclast differentiation under estrogen-deficient conditions. Methods An ovariectomized rat model was used to evaluate the anti-osteoporotic effects of GNS in vivo. Bone microarchitecture and osteoclast activity were assessed using micro-CT, histological staining, ELISA, and western blotting. Serum and fecal metabolite profiling was performed by UPLC-MS/MS to identify exposure-related compounds. Candidate compounds were screened in RAW264.7 osteoclast differentiation models. Public transcriptomic datasets were integrated to identify key regulatory genes associated with osteoclastogenesis. CRISPR/Cas9-mediated knockout, molecular docking, microscale thermophoresis , qPCR, immunofluorescence, and western blot analyses were performed for mechanistic validation. Results GNS significantly improved trabecular bone microarchitecture and reduced osteoclast activity in OVX rats. Exposure profiling identified adenosine, phellodendrine, and jatrorrhizine as prototype compounds in both serum and feces, whereas -magnoflorine was detected as a prototype in feces and as a demethylated metabolite in serum, indicating pharmacologically relevant MAG-related exposure. Functional screening identified -MAG as the most potent inhibitor of osteoclast differentiation in vitro. Integrated transcriptomic analyses revealed that CCDC88A was an early-response gene associated with osteoporosis progression and osteoclast differentiation. CCDC88A deficiency attenuated osteoclastogenesis and altered CCDC88A-associated signaling responses. Moreover, molecular docking and MST analyses supported a direct interaction between -MAG and CCDC88A, while CCDC88A depletion abolished the additional inhibitory effects of -MAG on osteoclast differentiation. Conclusion GNS effectively alleviated estrogen deficiency-associated bone loss by suppressing osteoclast activation. -MAG was identified as an exposure-related bioactive constituent, and its anti-osteoclast effects were mediated through a CCDC88A-dependent regulatory mechanism. These findings provide new insights into osteoclast regulation and highlight GNS-derived compounds as potential therapeutic candidates for postmenopausal osteoporosis.收起

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