Muscone Ameliorates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κb Ligand-Induced Osteoclastogenesis by Suppressing TNF Receptor–Associated Factor 6-Mediated Signaling Pathways

Frontiers in Pharmacology

Xiao Zhai¹  Yingchuan Zhao¹  Jian Zhao¹  Ming Li¹  Xiaozhao Wei¹  Yushu Bai¹  Mingyuan Yang¹  Yilin Yang¹  Bo Li¹  Xiaoyi Zhou¹  Kai Chen¹  Chunyou Huang²  Chen He²  Zijun Yan²  Mengxi Cai² 

[1] Department of Orthopedics, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China;Graduate Management Unit, Shanghai Changhai Hospital, Navy Medical University, Shanghai, China;

关键词: muscone;    postmenopausal osteoporosis;    osteoclasts;    RANK;    TRAF6;   

DOI  :  10.3389/fphar.2020.00348

来源: DOAJ

【 摘 要 】

Postmenopausal osteoporosis is caused by the deficiency of estrogen, which breaks bone homeostasis and induces levels of pro-inflammatory cytokines. Muscone is a potent anti-inflammatory agent and is used to treat bone fracture in traditional Chinese medicine. However, its anti-osteoclastogenic effects remain unclear. For in vitro study, morphology tests of osteoclastogenesis were firstly performed. And then, factors in RANK-induced NF-κB and MAPK pathways were examined by RT-PCR and Western blot, and the binding of TNF receptor–associated factor (TRAF)6 to RANK was inspected by coimmunoprecipitation and immunofluorescence staining. For in vivo experiments, C57BL/6 ovariectomized (OVX) mice were used for detection, including H&E staining, TRAP staining, and micro CT. As a result, muscone reduced OVX-induced bone loss in mice and osteoclast differentiation in vitro, by inhibiting TRAF6 binding to RANK, and then suppressed NF-κB and MAPK signaling pathways. The expression of the downstream biomarkers was finally inhibited, including NFATc1, CTR, TRAP, cathepsin K, and MMP-9. The inflammatory factors, TNF-a and IL-6, were also reduced by muscone. Taken together, muscone inhibited the binding of TRAF6 to RANK induced by RANKL, thus blocking NF-kB and MAPK pathways, and down-regulating related gene expression. Finally, muscone inhibited osteoclastogenesis and osteoclast function by blocking RANK-TRAF6 binding, as well as downstream signaling pathways in vitro. Muscone also reduced ovariectomy-induced bone loss in vivo.

【 授权许可】

Unknown