title: Alexidine Dihydrochloride Attenuates Osteoclast Formation and Bone Resorption and Protects Against LPS-Induced Osteolysis.
abstract: Aseptic loosening and periprosthetic infection leading to inflammatory osteolysis is a major complication associated with total joint arthroplasty (TJA). The liberation of bacterial products and/or implant-derived wear particles activates immune cells that produce pro-osteoclastogenic cytokines that enhance osteoclast recruitment and activity, leading to bone destruction and osteolysis. Therefore, agents that prevent the inflammatory response and/or attenuate excessive osteoclast (OC) formation and bone resorption offer therapeutic potential by prolonging the life of TJA implants. Alexidine dihydrochloride (AD) is a bisbiguanide compound commonly used as an oral disinfectant and in contact lens solutions. It possesses antimicrobial, anti-inflammatory and anticancer properties; however, its effects on OC biology are poorly described. Here, we demonstrate that AD inhibits OC formation and bone resorption in vitro and exert prophylatic protection against LPS-induced osteolysis in vivo. Biochemical analysis demonstrated that AD suppressed receptor activator of NF-κB ligand (RANKL)-induced activation of mitogen-activated protein kinases (ERK, p38, and JNK), leading to the downregulation of NFATc1. Furthermore, AD disrupted F-actin ring formation and attenuated the ability of mature OC to resorb bone. Collectively, our findings suggest that AD may be a promising prophylactic anti-osteoclastic/resorptive agent for the treatment of osteolytic diseases caused by excessive OC formation and function.
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Australia.|Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Australia.
authors.forename: Junjie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Australia.
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Ng
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: An
authors.initials: A
authors.lastname: Qin
authors.affiliation: Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, 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, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Australia.
authors.forename: Ming H
authors.initials: MH
authors.lastname: Zheng
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Crawley, Australia.
authors.forename: Tak S
authors.initials: TS
authors.lastname: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001645:Biguanides / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000473:pathology; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010014:Osteolysis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D053245:RANK Ligand / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D012886:Skull / Q000473:pathology
chemical_list: D001645:Biguanides; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D020928:Mitogen-Activated Protein Kinases; C001570:alexidine
keywords: ALEXIDINE DIHYDROCHLORIDE; BONE RESORPTION; MAPK AND NFATc1 SIGNALING PATHWAYS; OSTEOCLAST; OSTEOLYSIS