title: Natural Germacrane Sesquiterpenes Inhibit Osteoclast Formation, Bone Resorption, RANKL-Induced NF-κB Activation, and IκBα Degradation.
abstract: Osteolytic bone diseases are commonly presented with enhanced osteoclast formation and bone resorption. Sesquiterpene lactone natural compounds have been found to possess anti-inflammatory and immune-modulation effects. Here, we identified three germacrane sesquiterpenes using computer-based virtual screening for the structural similarity with sesquiterpene lactone, parthenolide. We showed that natural germacrane sesquiterpene compounds A, B, and C inhibit osteoclast formation and bone resorption in a dose-dependent manner, with relative potency compound A > compound C > compound B based on their equimolar concentrations. Mechanistic studies by Luciferase reporter gene assay and Western blot analysis showed that germacrane sesquiterpene compound A inhibits RANKL-induced activation of NF-κB and IκBα degradation. This study reveals that natural germacrane sesquiterpene compounds are inhibitors for osteoclast formation and bone resorption, and provides evidence that naturally-occurring compounds might be beneficial as alternative medicine for the prevention and treatment of osteolysis.
authors.affiliation: Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China. qinqinsn@163.com.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Qin
authors.affiliation: School of Dentistry, University of Western Australia, Perth, WA 6009, Australia. estabelle.ang@uwa.edu.au.
authors.forename: Estabelle
authors.initials: E
authors.lastname: Ang
authors.affiliation: Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China. Libingdai@126.com.
authors.forename: Libing
authors.initials: L
authors.lastname: Dai
authors.affiliation: Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China. dryang1192@tom.com.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China. yedongping927@126.com.|School of Pathology and Laboratory Medicine, the University of Western Australia, Perth, WA 6009, Australia. yedongping927@126.com.
authors.forename: Dongping
authors.initials: D
authors.lastname: Ye
authors.affiliation: Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China. honghchen@21cn.com.
authors.forename: Honghui
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Pathology and Laboratory Medicine, the University of Western Australia, Perth, WA 6009, Australia. 20463692@student.uwa.edu.au.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: School of Pathology and Laboratory Medicine, the University of Western Australia, Perth, WA 6009, Australia. 21159333@student.uwa.edu.au.
authors.forename: Mingli
authors.initials: M
authors.lastname: Yang
authors.affiliation: School of Pathology and Laboratory Medicine, the University of Western Australia, Perth, WA 6009, Australia. dian.teguh@research.uwa.edu.au.
authors.forename: Dian
authors.initials: D
authors.lastname: Teguh
authors.affiliation: Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. rxtan@nju.edu.cn.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: Research Center for Drug Discovery (RCDD), School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China. junxu@biochemomes.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Pathology and Laboratory Medicine, the University of Western Australia, Perth, WA 6009, Australia. jennifer.tickner@uwa.edu.au.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, the University of Western Australia, Perth, WA 6009, Australia. nanthan.pavlos@uwa.edu.au.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
authors.affiliation: Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou 510220, China. jiake.xu@uwa.edu.au.|School of Pathology and Laboratory Medicine, the University of Western Australia, Perth, WA 6009, Australia. jiake.xu@uwa.edu.au.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D001688:Biological Products / Q000494:pharmacology*; D001862:Bone Resorption / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism*; D045788:Sesquiterpenes, Germacrane / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D053245:RANK Ligand; D045788:Sesquiterpenes, Germacrane; D000072000:NF-KappaB Inhibitor alpha
keywords: IκBα; NF-κB; RANKL; bone resorption; germacrane sesquiterpenes; osteoclastogenesis