Endoplasmic reticulum stress-mediated inflammatory signaling pathways within the osteolytic periosteum and interface membrane in particle-induced osteolysis.

Guoyin Liu,Jianning Zhao,Jianmin Chen,Jiangning Chen,Junfeng Zhang,Yunfan Ti,Naicheng Liu,Yuansheng Xu

doi:10.1007/s00441-015-2205-9

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 Ca2+). 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 Ca2+ 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.

Highlights

Total joint replacement by the implantation of a permanently in-dwelling artificial prosthesis is a revolutionary surgical process for enhancing the agility of a patient with joint dysfunction (Klawitter et al 2011; Rubak et al 2014; Wooley and Schwarz 2004)
Consistent with the micro-CT quantitation, histological analysis demonstrated that 4-phenylbutyric acid (4-PBA) cotreatment significantly decreased the bone resorption induced by wear particles, whereas the osteolysis areas were markedly increased after TiNPs or the CoNPs and Tg combination (Fig. 1a’–h’)
With the improved comprehension of the molecular and cellular biological processes involved in particle-induced osteolysis, pharmacological interventions targeting inflammation and osteoclastogenesis have emerged as promising approaches to recognize this detrimental process and to ameliorate the deterioration of artificial prosthesis at the molecular level (Chen et al 2012; Goodman et al 2005; Ren et al 2004, 2006a, 2010; Yang et al 2012)

Summary

Introduction

Total joint replacement by the implantation of a permanently in-dwelling artificial prosthesis is a revolutionary surgical process for enhancing the agility of a patient with joint dysfunction (Klawitter et al 2011; Rubak et al 2014; Wooley and Schwarz 2004). Wear particles originating at the prosthesis interface can become distributed along the periprosthetic ambience and can occupy neighboring tissues in which they are phagocytosed by tissue-resident cells (Jasty and Smith 1992) These activated cells secrete an array of pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL1β], and IL-6), osteoclastogenic molecules (vascular endothelial growth factor [VEGF], osteoprotegerin OPG, receptor activator of nuclear kaapa B [RANKL] and macrophage/colonystimulating factor [M-CSF]) and other mediators of inflammation. This exacerbates the osteolytic responses via multiple biological functions, including the progression of an aggressive interface membrane adjacent to the bone, the differentiation of macrophages into lacunar bone-resorbing osteoclasts and the emancipation of the cytokines mentioned above to attract and enlist additional inflammatory cells that liberate more pro-inflammatory cytokines, osteoclastogenic cytokines and other mediators of inflammation. Considerable amounts of osteoclast precursor cells and osteoclasts are enlisted and/or activated to absorb the bone, a process that leads to local progressive bone destruction and prosthesis loosening

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Conclusion