title: Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption.
abstract: Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis.
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, The People's Republic of China.
authors.forename: An
authors.initials: A
authors.lastname: Qin
authors.forename: Tak S
authors.initials: TS
authors.lastname: Cheng
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lin
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.forename: Shek M
authors.initials: SM
authors.lastname: Chim
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.forename: Ming Hao
authors.initials: MH
authors.lastname: Zheng
authors.forename: Ke Rong
authors.initials: KR
authors.lastname: Dai
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019643:Arthroplasty, Replacement / Q000009:adverse effects; D016764:Cell Polarity / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D010014:Osteolysis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053245:RANK Ligand / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012886:Skull / Q000166:cytology; D014025:Titanium / Q000009:adverse effects*; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D053245:RANK Ligand; D012459:Salicylates; C574373:saliphenylhalamide; D014025:Titanium; D048049:Extracellular Signal-Regulated MAP Kinases; D025262:Vacuolar Proton-Translocating ATPases