title: SIRT1 protects osteoblasts against particle-induced inflammatory responses and apoptosis in aseptic prosthesis loosening.
abstract: We hypothesized that SIRT1 downregulation in osteoblasts induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total joint arthroplasty failure. In the present study, the expression of SIRT1 was examined in osteoblasts treated with TiAl6V4 particles (TiPs) and CoCrMo particles (CoPs) from materials used in prosthetics and specimens from PIO animal models. To address whether SIRT1 downregulation triggers inflammatory responses and apoptosis in osteoblasts, the effect of a SIRT1 activator, resveratrol on the expression of inflammatory cytokines and apoptosis in particle-treated osteoblasts was tested. The results demonstrated that SIRT1 expression was significantly downregulated in particle-treated osteoblasts and PIO animal models. Both pharmacological activation and overexpression of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines and osteoblast apoptosis through NF-κB and p53 signaling, respectively. Furthermore, in PIO animal models, resveratrol significantly reduced the severity of osteolysis. Collectively, the results of the present study indicated that SIRT1 plays a vital role in the pathogenesis of aseptic loosening, and further treatment targeted at SIRT1 possibly lead to novel approaches for prevention of aseptic prosthesis loosening.
  
  
  
  Aseptic loosening is the most common cause of total hip arthroplasty (THA) and total knee arthroplasty (TKA) failure and revision surgery. However, there is still no effective therapeutic target in the clinical treatment. Besides, the underlying mechanism of aseptic loosening is largely unknown. The result of our study indicated that SIRT1 has the ability to effectively regulate the wear particle-induced inflammatory responses, apoptosis, osteolysis in particle-stimulated osteoblasts and particle-induced osteolysis animal models. Our study provides a potential target for the prevention and treatment of aseptic loosening and further investigated the underlying mechanism of aseptic loosening, which may make contribution to decrease the incidence of THA and TKA failure in the clinical practice.
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China; Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, PR China. Electronic address: dengzhantao_med@163.com.
authors.forename: Zhantao
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China. Electronic address: wangzhenheng1987@163.com.
authors.forename: Zhenheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, PR China. Electronic address: 18757851015@163.com.
authors.forename: Jiewen
authors.initials: J
authors.lastname: Jin
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, PR China. Electronic address: yongwang@nju.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China. Electronic address: bnrbnr@sina.com.
authors.forename: Nirong
authors.initials: N
authors.lastname: Bao
authors.affiliation: Center for Translational Medicine, Nanjing University Medical School, Nanjing, Jiangsu, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, PR China. Electronic address: qian_gao@nju.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China. Electronic address: zhaojianning.0207@163.com.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000497:Alloys; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology*; D010014:Osteolysis / Q000378:metabolism / Q000473:pathology; D011475:Prosthesis Failure / Q000009:adverse effects*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D014025:Titanium / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000497:Alloys; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C031462:titanium alloy (TiAl6V4); D014025:Titanium; D056564:Sirtuin 1
keywords: Apoptosis; Aseptic loosening; Inflammatory responses; Osteoblast; Osteolysis; SIRT1