title: The prevention of titanium-particle-induced osteolysis by OA-14 through the suppression of the p38 signaling pathway and inhibition of osteoclastogenesis.
abstract: Wear-particle-induced osteolysis leads to prosthesis loosening, which is one of the most common causes of joint-implant failure, a problem that must be fixed using revision surgery. Thus, a potential treatment for prosthetic loosening is focused on inhibiting osteoclastic bone resorption, which prevents wear-particle-induced osteolysis. In this study, we synthesized a compound named OA-14 (N-(3- (dodecylcarbamoyl)phenyl)-1H-indole-2-carboxamide) and examined how OA-14 affects titanium (Ti)-particle-induced osteolysis and osteoclastogenesis. We report that OA-14 treatment protected against Ti-particle-induced osteolysis in a mouse calvarial model. Interestingly, the number of tartrate-resistant acid phosphatase-positive osteoclasts decreased after treatment with OA-14 in vivo, which suggested that OA-14 inhibits osteoclast formation. To test this hypothesis, we conducted in vitro studies, and our results revealed that OA-14 markedly diminished osteoclast differentiation and osteoclast-specific gene expression in a dose- and time-dependent manner. Moreover, OA-14 suppressed osteoclastic bone resorption and F-actin ring formation. Furthermore, we determined that OA-14 inhibited osteoclastogenesis by specifically blocking the p38-Mitf-c-fos-NFATc1 signaling cascade induced by RANKL (ligand of receptor activator of nuclear factor κB). Collectively, our results suggest that the compound OA-14 can be safely used for treating particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function.
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tian
authors.affiliation: The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Clinical Medical College of Nanjing Medical University, Jiangsu, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors.forename: Zhanying
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Zanjing
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Haowei
authors.initials: H
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Xuqiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Zhengxiao
authors.initials: Z
authors.lastname: Ouyang
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Tang
authors.affiliation: The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Clinical Medical College of Nanjing Medical University, Jiangsu, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Perth, Australia.
authors.forename: Minghao
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Kerong
authors.initials: K
authors.lastname: Dai
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Perth, Australia. Electronic address: dr.qinan@gmail.com.
authors.forename: An
authors.initials: A
authors.lastname: Qin
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China. Electronic address: yyu@zju.edu.cn.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address: zhuzhenan2006@126.com.
authors.forename: Zhenan
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001862:Bone Resorption / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007211:Indoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010014:Osteolysis / Q000139:chemically induced / Q000188:drug therapy*; D053245:RANK Ligand / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D014025:Titanium / Q000009:adverse effects*
chemical_list: D000199:Actins; D001549:Benzamides; D007211:Indoles; D007527:Isoenzymes; C000597305:N-(3-(dodecylcarbamoyl)phenyl)-1H-indole-2-carboxamide; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014025:Titanium; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: MAP kinase; NFATc1; OA-14; Osteoclast; Osteolysis; Total joint arthroplasty