title: Autophagy mediated TiAl₆V₄ particle-induced peri-implant osteolysis by promoting expression of TNF-α.
abstract: Peri-prosthetic osteolysis and the consequent aseptic loosening constitute the most common reason for total joint arthroplasty failure and surgical revision. Although numerous studies suggest that pro-inflammatory cytokines induced by wear particles is involved in the pathological process of aseptic loosening, the underlying mechanism linking wear particles to pro-inflammatory cytokines remains to be illustrated. In the present study, we investigated the effect of autophagy on TNF-α secretion induced by TiAl6V4 particles (TiPs) in macrophages and in a calvarial resorption animal model. Our study demonstrated that TiPs activated autophage in macrophages and particle-induced osteolysis animal models as well as periprosthetic membranes of patients with aseptic loosening. The autophagy inhibitor 3-MA (3-methyladenine) could dramatically reduce TiPs-induced TNF-α expression both in macrophages and in membranes from animal models. Furthermore, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Collectively, these results suggest that autophagy plays a key role in TiPs-induced osteolysis by promoting TNF-α expression and that blocking autophagy may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Naicheng
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Zhenheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Tongguo
authors.initials: T
authors.lastname: Shi
authors.affiliation: Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China. Electronic address: zhaojianning.0207@163.com.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000368:Aged; D000369:Aged, 80 and over; D000497:Alloys; D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010014:Osteolysis / Q000139:chemically induced*; D011475:Prosthesis Failure; D014025:Titanium / Q000009:adverse effects / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D055114:X-Ray Microtomography; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000497:Alloys; D014409:Tumor Necrosis Factor-alpha; C031462:titanium alloy (TiAl6V4); C025946:3-methyladenine; D014025:Titanium; D048051:p38 Mitogen-Activated Protein Kinases; D000225:Adenine
keywords: Aseptic loosening; Autophagy; Macrophages; Osteolysis; Wear particles