title: Expression of XBP1s in fibroblasts is critical for TiAl6V4particle-induced RANKL expression and osteolysis.
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 expression of Receptor activation of nuclear factor (NF)-kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle-induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl6V4particle (TiPs)-induced XBP1s (spliced form of X-box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri-implant membrane, animal models, and TiPs-stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate-resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro-computed tomography (micro-CT) with three-dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models, and TiPs-stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs-induced of RANKL expression in fibroblasts, and down regulating XBP1s may represent a potential therapy for wear particle-induced osteolysis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:752-759, 2017.
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Zhenheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Naicheng
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
authors.forename: Tongguo
authors.initials: T
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Gan
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Nirong
authors.initials: N
authors.lastname: Bao
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000368:Aged; D000497:Alloys; D000818:Animals; D019644:Arthroplasty, Replacement, Hip; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010010:Osteoclasts / Q000502:physiology; D010014:Osteolysis / Q000378:metabolism*; D011475:Prosthesis Failure; D053245:RANK Ligand / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D014025:Titanium / Q000737:chemistry*; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D000497:Alloys; D053245:RANK Ligand; D034741:RNA, Small Interfering; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C031462:titanium alloy (TiAl6V4); D014025:Titanium
keywords: RANKL; TiAl6V4 particles; XBP1s; fibroblasts; osteolysis