title: Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops.
abstract: Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption, and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-κB and Ca(2+)/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis.
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.|The Center for Heart Development, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Human Normal University, Changsha, Human 410081, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xie
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Huayun
authors.initials: H
authors.lastname: Deng
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xueyun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Chunbing
authors.initials: C
authors.lastname: Zheng
authors.affiliation: The Center for Heart Development, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Human Normal University, Changsha, Human 410081, China.
authors.forename: Xiushan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.|Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D005419:Flavonoids; D011427:Propiophenones; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C104536:xanthohumol