文献类型：期刊文献

英文题名：(+)-Magnoflorine suppresses osteoclastogenesis by regulating CCDC88A-associated signaling networks in estrogen-deficient osteoporosis

作者：Zhang, Wei[1,2];Wang, An-zhu[3,4];Li, Xiang[5];Kang, Meng-jiao[6];Liu, Qian[7,8];Tian, Jing-ru[5];Li, Xiang-yan[9];Wang, Ze-yu[9,10];Zhao, Jin-yue[11];Fan, Jia-xing[12];Wang, Shan[13,14];Qin, Li-hua[5];Tong, Xiao-lin[1];Zhao, Lin-hua[1,15]

第一作者：张维;张伟;Zhang, Wei

通信作者：Tong, XL[1];Zhao, LH[1];Qin, LH[2];Wang, S[3];Zhao, LH[4]

机构：[1]China Acad Chinese Med Sci, Guanganmen Hosp, Inst Metab Dis, Beijing, Peoples R China;[2]Gansu Univ Chinese Med, Sch Basic Med, Lanzhou, Gansu, Peoples R China;[3]Shandong First Med Univ, Minist Educ, Key Lab Endocrine Glucose & Lipids Metab & Brain A, Jinan, Peoples R China;[4]Shandong First Med Univ, Shandong Prov Hosp, Dept Endocrinol, Jinan, Peoples R China;[5]Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Human Anat Histol & Embryol, Beijing, Peoples R China;[6]Zhejiang Chinese Med Univ, Sch Clin Med 1, Hangzhou, Zhejiang, Peoples R China;[7]Fourth Mil Med Univ, Natl Clin Res Ctr Oral Dis, State Key Lab Oral& Maxillofacial Reconstruct & Re, Shaanxi Key Lab Stomatol, Xian, Peoples R China;[8]Fourth Mil Med Univ, Sch Stomatol, Dept Orthodont, Xian, Peoples R China;[9]Changchun Univ Chinese Med, Minist Educ, Northeast Asia Res Inst Tradit Chinese Med, Changchun, Peoples R China;[10]Jilin Prov Key Lab Biomacromol Chinese Med, Key Lab Act Subst & Biol Mech Ginseng Efficacy, Changchun, Peoples R China;[11]Changchun Univ Chinese Med, Affiliated Hosp, Changchun, Peoples R China;[12]Jinzhou Med Univ, Sch & Hosp Stomatol, Jinzhou, Peoples R China;[13]China Japan Friendship Hosp, Inst Clin Med Sci, Beijing, Peoples R China;[14]China Japan Friendship Hosp, Natl Ctr Integrat Med, Beijing, Peoples R China;[15]Changchun Univ Chinese Med, Affiliated Hosp, Dept Endocrinol, Changchun, Jilin, Peoples R China

第一机构：China Acad Chinese Med Sci, Guanganmen Hosp, Inst Metab Dis, Beijing, Peoples R China

通信机构：[1]corresponding author), China Acad Chinese Med Sci, Guanganmen Hosp, Inst Metab Dis, Beijing, Peoples R China;[2]corresponding author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Human Anat Histol & Embryol, Beijing, Peoples R China;[3]corresponding author), China Japan Friendship Hosp, Inst Clin Med Sci, Beijing, Peoples R China;[4]corresponding author), Changchun Univ Chinese Med, Affiliated Hosp, Dept Endocrinol, Changchun, Jilin, Peoples R China.

年份：2026

卷号：161

外文期刊名：PHYTOMEDICINE

收录：;Scopus(收录号：2-s2.0-105047622326);WOS:【SCI-EXPANDED(收录号:WOS:001854230100001)】；

基金：This study was supported by Scientific and Technological Innovation project of China Academy of Chinese Medical Sciences (CI2021B008, China), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No: ZYYCXTD-D-202001), Dose-Effect Study of Prescriptions of China Association of Chinese Medicine (No: 202428-003, China).

语种：英文

外文关键词：Postmenopausal osteoporosis; Osteoclast differentiation; (+)-Magnoflorine; CCDC88A; WNT/beta-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 (GNS), identify its pharmacologically relevant absorbed constituents, and investigate the molecular mechanisms underlying its regulation of osteoclast differentiation under estrogen-deficient conditions. Methods: An ovariectomized (OVX) 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 exposurerelated compounds. Candidate compounds were screened in RAW264.7 osteoclast differentiation models. Public transcriptomic datasets (GSE230665 and GSE246769) were integrated to identify key regulatory genes associated with osteoclastogenesis. CRISPR/Cas9-mediated knockout, molecular docking, microscale thermo-phoresis (MST), 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 symbolscript (MAG) was detected as a prototype in feces and as a demethylated metabolite in serum, indicating pharmacologically relevant MAG-related exposure. Functional screening iden-tified symbolscript as the most potent inhibitor of osteoclast differentiation in vitro. Integrated transcriptomic an-alyses 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 symbolscript and CCDC88A, while CCDC88A depletion abolished the additional inhibitory effects of symbolscript on osteoclast differentiation. Conclusion: GNS effectively alleviated estrogen deficiency-associated bone loss by suppressing osteoclast acti-vation. symbolscript 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 post-menopausal osteoporosis.