title: Triptolide inhibits osteoclast formation, bone resorption, RANKL-mediated NF-қB activation and titanium particle-induced osteolysis in a mouse model.
abstract: The RANKL-induced NF-κB signaling pathway is required for osteoclast formation and function. By screening for compounds that inhibit RANKL-induced NF-κB activation using a luciferase reporter gene assay in RAW264.7 cells, we identified triptolide (PG490), as a candidate compound targeting osteoclast differentiation and osteoclast-mediated osteolysis. Triptolide (PG490) is an active compound of the medicinal herb Tripterygium wilfordii Hook F (TWHF) or Lei Gong Teng with known anti-inflammatory properties. We found that triptolide inhibited osteoclastogenesis and bone resorption, as well as RANKL-induced NF-қB activities as monitored by luciferase reporter gene assays and the nuclear translocation of p65. In vivo studies showed that triptolide attenuates titanium-induced osteolysis and osteoclast formation in a mouse calvarial model. Considering that drugs which protect against localized bone loss are critically needed for the effective treatment of particle-induced osteolysis, our data suggest that triptolide might have therapeutic potential for the treatment of bone lytic diseases caused by prosthetic wear particles.
authors.affiliation: Orthopaedic Department, Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Huang
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia.
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; Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Huafei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pavlos
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Shek Man
authors.initials: SM
authors.lastname: Chim
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia; Research Centre for Regenerative Medicine, Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China, 530021.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Research Centre for Regenerative Medicine, Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China, 530021.
authors.forename: Jinmin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou, China, 510632.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Institute of Functional Biomolecules, Medical School, Nanjing University, Nanjing, China, 210093.
authors.forename: Ren Xiang
authors.initials: RX
authors.lastname: Tan
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC 3083, Australia.
authors.forename: Jiming
authors.initials: J
authors.lastname: Ye
authors.affiliation: Research Center for Drug Discovery (RCDD), School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou, China, 510006.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Dentistry, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Estabelle S
authors.initials: ES
authors.lastname: Ang
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia; Program of Nutrition and Bone & Joint Health, Nestlé R&D (China) Ltd. Building 5, No. 5 Dijin Road, Haidian District, Beijing, China, 100095.
authors.forename: Haotian
authors.initials: H
authors.lastname: Feng
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia. Electronic address: jiake.xu@uwa.edu.au.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: Orthopaedic Department, Memorial Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: dingyue36@126.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002460:Cell Line; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010014:Osteolysis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism*; D014025:Titanium / Q000633:toxicity*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D053245:RANK Ligand; C498144:Rela protein, mouse; C505689:Tnfsf11 protein, mouse; D051996:Transcription Factor RelA; C001899:triptolide; D014025:Titanium
keywords: NF-κB; Osteoclastogenesis; Osteolysis; RANKL; Titanium particle; Triptolide