Aggravation of inflammatory response by costimulation with titanium particles and mechanical perturbations in osteoblast- and macrophage-like cells

Abstract

The interface between bone tissue and metal implants undergoes various types of mechanical loading, such as strain, compression, fluid pressure, and shear stress, from daily activities. Such mechanical perturbations create suboptimal environments at the host bone-implant junction, causing an accumulation of wear particles and debilitating osseous integration, potentially leading to implant failure. While many studies have focused on the effect of particles on macrophages or osteoprogenitor cells, differential and combined effects of mechanical perturbations and particles on such cell types have not been extensively studied. In this study, macrophages and osteoprogenitor cells were subjected to physiological and superphysiological mechanical stimuli in the presence and absence of Ti particles with the aim of simulating various microenvironments of the host bone-implant junction. Macrophages and osteoprogenitor cells were capable of engulfing Ti particles through actin remodeling and also exhibited changes in mRNA levels of proinflammatory cytokines under certain conditions. In osteoprogenitor cells, superphysiological strain increased proinflammatory gene expression; in macrophages, such mechanical perturbations did not affect gene expression. We confirmed that this phenomenon in osteoprogenitor cells occurred via activation of the ERK1/2 signaling pathway as a result of damage to the cytoplasmic membrane. Furthermore, AZD6244, a clinically relevant inhibitor of the ERK1/2 pathway, mitigated particle-induced inflammatory gene expression in osteoprogenitor cells and macrophages. This study provides evidence of more inflammatory responses under mechanical strains in osteoprogenitor cells than macrophages. Phagocytosis of particles and mechanical perturbation costimulate the ERK1/2 pathway, leading to expression of proinflammatory genes.

Scaling of titanium implants entrains inflammation-induced osteolysis

“…The results of our study are in accordance with the literature on innate immune responses to Ti particles, which have been extensively investigated, mainly with regard for the particles shed by orthopedic Ti prostheses1011131416. In our study, US scaling of Ti surfaces induced the release of particles that stimulated the secretion of pro-inflammatory cytokines.…”

Gene Expression in Osteolysis: Review on the Identification of Altered Molecular Pathways in Preclinical and Clinical Studies

“…Mouse macrophage cell lines (RAW264.7) were the most used [4,6,27,28,29,30,31,32,33,34,35,36,37], followed by OB precursors derived from mouse calvaria (MC3T3-E1) [27,28,38,39,40,41] and human (Saos-2 and MG-63) [1,42,43] or rat (ROS 17/2.8) [44] osteosarcoma and monocitic (THP-1) [20,45,46] cell lines. In addition, other studies also used primary cells: mouse [28,47] or human [42,48] OBs, mouse or rat bone-marrow-derived macrophages (BMM) [28,49,50,51], human MSCs [39,52], mouse [47] or human [53] FBs and mouse peritoneal macrophages [54]. In one study, mouse calvaria [4] were cultured in toto.…”

“…In one study, mouse calvaria [4] were cultured in toto. Regarding the different wear particles used, Ti [4,6,27,28,29,30,31,32,33,38,39,42,45,50,52,53] was the most employed, followed by PE [20,34,37,43,47,48], PMMA [36,41,51] and Co-Cr alloy [1,40,46]. Three studies compared Ti effects with PMMA [49], zirconia (ZrO 2 ) [54] and aluminia ceramic (CE) [34] and one compared PE and hydroxyapatite (HA) particles [44].…”

“…These changes were accompanied by an increase in Nitric Oxide Synthase 2 (NOS 2 ), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and MMP9 gene expression and a reduction in genes linked to superoxide dismutase pathways [4,27,28,29,30,33,50]. One study showed an increase in TNFα, C-X-C motif chemokine 10 (CXCL10), C–C chemokine receptor type 7 (CCR7) and IL10 gene expression with microparticles of Ti in THP-1 cells in a dose-dependent manner.…”

“…In cells of the osteoblastic lineage, Ti particles induced an increase in the pro-inflammatory genes and a decrease in Osteoprotegerin (OPG) gene observed in macrophagic cells and in CB2 [27,28,38,39,42]. In addition, one study analyzed osteogenesis and apoptotic pathways with microarray in hMSCs, showing an up-regulation of genes of pro-apoptotic proteins (Bcl-2-associated death promoter (BAD), Cluster of Differentiation 70 (CD70), B-cell lymphoma 2 (BCL2) and a down-regulation of anti-apoptotic and osteogenesis genes, encoding for Cartilage oligomeric matrix protein (COMP), Fibroblast Growth Factor Receptor 2 (FGFR2), Insulin-like growth factor 1 (IGF-1), Bone morphogenetic protein 6 (BMP6), Collagens (COLLs), (sex determining region Y)-box 9 (SOX9) and OPG [52].…”