title: Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways.
abstract: Activation of NF-κB and MAPK/activator protein 1 (AP-1) signaling pathways by receptor activator NF-κB ligand (RANKL) is essential for osteoclast activity. Targeting NF-κB and MAPK/AP-1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases. In this study we examined the effects of maslinic acid (MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL-induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, MA inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis-related marker gene expression, including TRACP, MMP9, c-Src, CTR, and cathepsin K. Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage. In ovariectomized mice, administration of MA prevented ovariectomy-induced bone loss by inhibiting osteoclast activity. At molecular levels, MA abrogated the phosphorylation of MAPKs and AP-1 activity, inhibited the IκBα phosphorylation and degradation, blocked NF-κB/p65 phosphorylation, nuclear translocation, and DNA-binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6. Together our data demonstrate that MA suppresses RANKL-induced osteoclastogenesis through NF-κB and MAPK/AP-1 signaling pathways and that MA is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Li
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yang
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.forename: Lipeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Chunbing
authors.initials: C
authors.lastname: Zheng
authors.forename: Wenwei
authors.initials: W
authors.lastname: Qiu
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.forename: Xiu
authors.initials: X
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000201:enzymology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010052:Ovariectomy; D053245:RANK Ligand / Q000494:pharmacology*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives
chemical_list: D000199:Actins; D015415:Biomarkers; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D014315:Triterpenes; C412811:maslinic acid; D009828:Oleanolic Acid