title: Endoplasmic reticulum stress-mediated inflammatory signaling pathways within the osteolytic periosteum and interface membrane in particle-induced osteolysis.
abstract: Aseptic loosening secondary to periprosthetic inflammatory osteolysis results from the biological response to wear particles and is a leading cause of arthroplasty failure. The origin of this inflammatory response remains unclear. We aim to validate the definite link between endoplasmic reticulum (ER) stress and particle-induced inflammatory signaling pathways in periprosthetic osteolysis. We examine the histopathologic changes of osteolysis and the expression of specific biomarkers for ER-stress-mediated inflammatory signaling pathways (IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca(2+)). Moreover, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and osteoclastogenic molecules (VEGF, OPG, RANKL and M-CSF) were assessed in clinical interface membranes and murine periosteum tissues. We found wear particles to be capable of inducing ER stress in macrophages within clinical osteolytic interface membranes and murine osteolytic periosteum tissues and to be associated with the inflammatory response and osteoclastogenesis. Blocking ER stress with sodium 4-phenylbutyrate (4-PBA) results in a dramatic amelioration of particle-induced osteolysis and a significant reduction of ER-stress intensity. Simultaneously, this ER-stress blocker also lessens inflammatory cell infiltration, diminishes the capability of osteoclastogenesis and reduces the inflammatory response by lowering IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca(2+) levels. Thus, ER stress plays an important role in particle-induced inflammatory osteolysis and osteoclastogenic reactions. The pharmacological targeting of ER-stress-mediated inflammatory signaling pathways might be an appealing approach for alleviating or preventing particle-induced osteolysis in at-risk patients.
authors.affiliation: Department of Orthopaedics, Jinling Hospital affiliated to the School of Medicine, Nanjing University, Nanjing, 210093, China.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.|Department of Orthopaedics, Jingdu Hospital, Nanjing, 210002, China.
authors.forename: Guoyin
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Jinling Hospital affiliated to the School of Medicine, Nanjing University, Nanjing, 210093, China.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Naicheng
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Jingdu Hospital, Nanjing, 210002, China.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, Jinling Hospital affiliated to the School of Medicine, Nanjing University, Nanjing, 210093, China.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Yunfan
authors.initials: Y
authors.lastname: Ti
authors.affiliation: Department of Orthopaedics, Jinling Hospital affiliated to the School of Medicine, Nanjing University, Nanjing, 210093, China.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Jingdu Hospital, Nanjing, 210002, China. cjmlly@163.com.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Jinling Hospital affiliated to the School of Medicine, Nanjing University, Nanjing, 210093, China. jfzhang@nju.edu.cn.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China. jfzhang@nju.edu.cn.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Jinling Hospital affiliated to the School of Medicine, Nanjing University, Nanjing, 210093, China. zhaojianning.0207@163.com.|State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China. zhaojianning.0207@163.com.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000368:Aged; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008566:Membranes; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000009:adverse effects*; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000150:complications / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D053244:Osteoprotegerin / Q000378:metabolism; D010521:Periosteum / Q000000981:diagnostic imaging / Q000473:pathology*; D019736:Prostheses and Implants / Q000009:adverse effects; D011475:Prosthesis Failure; D053245:RANK Ligand / Q000378:metabolism; D011859:Radiography; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D018836:Inflammation Mediators; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D042461:Vascular Endothelial Growth Factor A
keywords: Aseptic loosening; Endoplasmic reticulum stress; Human; Inflammatory signaling pathways; Mouse; Osteoclastogenesis; Periprosthetic inflammatory osteolysis; Wear particles