title: Rifampin suppresses osteoclastogenesis and titanium particle-induced osteolysis via modulating RANKL signaling pathways.
abstract: Wear particles liberated from the surface of prostheses are considered to be main reason for osteoclast bone resorption and that extensive osteoclastogenesis leads to peri-implant osteolysis and subsequent prosthetic loosening. The aim of this study was to assess the effect of rifampin on osteoclastogenesis and titanium (Ti) particle-induced osteolysis. The Ti particle-induced osteolysis mouse calvarial model and bone marrow-derived macrophages (BMMs) were used. Rifampin, at dose of 10 or 50 mg/kg/day, was respectively given intraperitoneally for 14 days in vivo. The calvariae were removed and processed for Further histological analysis. In vitro, osteoclasts were generated from mouse BMMs with receptor activator of nuclear factor-κB ligand (RANKL) and the macrophage colony stimulating factor. Rifampin at different concentrations was added to the medium. The cell viability, tartrate-resistant acid phosphatase (TRAP) staining, TRAP activity and resorption on bone slices were analysis. Osteoclast-specific genes and RANKL-induced MAPKs signaling were tested for further study of the mechanism. Rifampin inhibited Ti-induced osteolysis and osteoclastogenesis in vivo. In vitro data indicated that rifampin suppressed osteoclast differentiation and bone resorption in a dose-dependent manner. Moreover, rifampin significantly reduced the expression of osteoclast-specific markers, including TRAP, cathepsin K, V-ATPase d2, V-ATPase a3, c-Fos, and nuclear factor of activated T cells (NFAT) c1. Further investigation revealed that rifampin inhibited osteoclast formation by specifically abrogating RANKL-induced p38 and NF-κB signaling. Rifampin had significant potential for the treatment of particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function.
authors.affiliation: Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, China; Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Kang
authors.affiliation: Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, China.
authors.forename: Chang-An
authors.initials: CA
authors.lastname: Guo
authors.affiliation: Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, China.
authors.forename: Wen-Shuai
authors.initials: WS
authors.lastname: Fan
authors.affiliation: Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Lian-Fu
authors.initials: LF
authors.lastname: Deng
authors.affiliation: Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, China. Electronic address: zuoqin_yan@163.com.
authors.forename: Zuo-Qin
authors.initials: ZQ
authors.lastname: Yan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010014:Osteolysis / Q000139:chemically induced*; D053245:RANK Ligand / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014025:Titanium / Q000633:toxicity*; D055114:X-Ray Microtomography; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D053245:RANK Ligand; D014025:Titanium; D048051:p38 Mitogen-Activated Protein Kinases; D012293:Rifampin
keywords: NF-κB; Osteolysis; P38; Rifampin; Wear particles