title: ER Stress Mediates TiAl6V4 Particle-Induced Peri-Implant Osteolysis by Promoting RANKL Expression in Fibroblasts.
abstract: Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the synovial fibroblasts present in the periprosthetic membrane are important targets of wear debris during osteolysis. However, the interaction mechanisms between the wear debris and fibroblasts remain largely unknown. In the present study, we investigated the effect of ER (endoplasmic reticulum) stress induced by TiAl6V4 particles (TiPs) in human synovial fibroblasts and calvarial resorption animal models. The expression of ER stress markers, including IRE1-α, GRP78/Bip and CHOP, were determined by western blot in fibroblasts that had been treated with TiPs for various times and concentration. To address whether ER stress was involved in the expression of RANKL, the effects of ER stress blockers (including 4-PBA and TUDCA) on the expression of RANKL in TiPs-treated fibroblasts were examined by real-time PCR, western blot and ELISA. Osteoclastogenesis was assessed by tartrate resistant acid phosphatase (TRAP) staining. Our study demonstrated that ER stress markers were markedly upregulated in TiPs-treated fibroblasts. Blocking ER stress significantly reduced the TiPs-induced expression of RANKL both in vitro and in vivo. Moreover, the inhibition of ER stress ameliorated wear particle-induced osteolysis in animal models. Taken together, these results suggested that the expression of RANKL induced by TiPs was mediated by ER stress in fibroblasts. Therefore, down regulating the ER stress of fibroblasts represents a potential therapeutic approach for wear particle-induced periprosthetic osteolysis.
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Zhenheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Naicheng
authors.initials: N
authors.lastname: Liu
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Tongguo
authors.initials: T
authors.lastname: Shi
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Gan
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qian
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Nirong
authors.initials: N
authors.lastname: Bao
authors.affiliation: Jinling Hospital, Department of Orthopaedics, School of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000497:Alloys; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D000069343:Bone-Implant Interface; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D010014:Osteolysis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000096:biosynthesis*; D014025:Titanium / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000497:Alloys; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; C031462:titanium alloy (TiAl6V4); D014025:Titanium