title: Thonzonium bromide inhibits RANKL-induced osteoclast formation and bone resorption in vitro and prevents LPS-induced bone loss in vivo.
abstract: Osteoclasts (OCs) play a pivotal role in a variety of lytic bone diseases including osteoporosis, arthritis, bone tumors, Paget's disease and the aseptic loosening of orthopedic implants. The primary focus for the development of bone-protective therapies in these diseases has centered on the suppression of OC formation and function. In this study we report that thonzonium bromide (TB), a monocationic surface-active agent, inhibited RANKL-induced OC formation, the appearance of OC-specific marker genes and bone-resorbing activity in vitro. Mechanistically, TB blocked the RANKL-induced activation of NF-κB, ERK and c-Fos as well as the induction of NFATc1 which is essential for OC formation. TB disrupted F-actin ring formation resulting in disturbances in cytoskeletal structure in mature OCs during bone resorption. Furthermore, TB exhibited protective effects in an in vivo murine model of LPS-induced calvarial osteolysis. Collectively, these data suggest that TB might be a useful alternative therapy in preventing or treating osteolytic diseases.
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Western Australia 6009, Australia; Department of Orthopaedics, Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Gao
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Euphemie
authors.initials: E
authors.lastname: Landao-Bassonga
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
authors.forename: An
authors.initials: A
authors.lastname: Qin
authors.affiliation: Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: James H
authors.initials: JH
authors.lastname: Steer
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Ming H
authors.initials: MH
authors.lastname: Zheng
authors.affiliation: Department of Orthopaedics, Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: dongyang6405@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Western Australia 6009, Australia. Electronic address: taksum.cheng@uwa.edu.au.
authors.forename: Tak S
authors.initials: TS
authors.lastname: Cheng
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D053245:RANK Ligand / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats
chemical_list: D000199:Actins; D008070:Lipopolysaccharides; D011743:Pyrimidines; D000644:Quaternary Ammonium Compounds; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C000609116:thonzonium bromide
keywords: Concanamycin A (PubChem CID: 3649143); NF-κB; NFATc1; Nigericin (PubChem CID: 34230); Osteoclast; Osteolysis; Thonzonium bromide; Thonzonium bromide (PubChem CID: 11102); Valinomycin (PubChem CID: 5649)