Down-Regulation of Procollagen α1[I] Messenger RNA by Titanium Particles Correlates with Nuclear Factor κB (NF-κB) Activation and Increased Rel A and NF-κB1 Binding to the Collagen Promoter

Roebuck, Kenneth A.; Vermes, Csaba; Carpenter, Laura Rocco; Fritz, Elizabeth A.; Narayanan, Ramesh; Glant, Tibor T.

doi:10.1359/jbmr.2001.16.3.501

Cited by 35 publications

(50 citation statements)

References 44 publications

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“…However, the antioxidant inhibitor, Nac, only inhibited the NF-KB binding induced by Ti particles. Previous studies showed that pyrrolidine dithiocarbamate (PDTC), another antioxidant inhibitor of NF-KB, also reduced the binding activity of NF-KB in Ti-exposed MG-63 osteoblastic cells [31]. Nac was also demonstrated to suppress the polymethylmethacrylate particulate activation of TNFa and IL-lP gene expression in macrophages 1251.…”

Section: Discussionmentioning

confidence: 99%

“…2A) due to a time interval required for phagocytosis-initiated signaling mechanism [31,40,43]. In particular, Ti particles enhanced binding of the p50/NF-~Bl and p65/RelA NF-KB subunits to the IL-8-specific KB promoter element [ lo], and the inhibitors of NF-KB activity, Nac and MG-132, both suppressed IL-8 protein secretion in Ti stimulated bone marrow derived osteoblasts [9].…”

Section: Discussionmentioning

confidence: 99%

“…On the average, 54% of Ti particles used in this study was smaller than 1 pm, and 94% were smaller than 3 pm in diameter [31,43]. The Limulus assay (E-Toxate; Sigma, St. Louis, MO), following the manufacturer's protocol, was applied to ensure Ti particles and culture conditions were endotoxin-free.…”

Section: Particlesmentioning

confidence: 99%

“…Nuclear protein extracts were prepared from MG-63 cells using an adapted method of Osborn et al [28] as previously described [31]. Specific NF-KB subunit activation was determined by commercially available ELISA specific for either the p50 (NF-KBI) or p65 (RelA) NF-KB subunit following the manufacture's protocol (Active Motif, Carlsbad, CA) using 3-7 pg of nuclear protein.…”

Section: Determination Of Nf-kb D N a Binding Activity And Nf-kb Subumentioning

confidence: 99%

“…NF-KB, a redox-sensitive transcription factor, can also be activated by reactive oxygen species (ROS) or oxidant-mediated stimuli, and ROS are associated with particles in vivo [8]. As a result, particle-challenged osteoblasts, macrophages, fibroblasts and osteoclasts exhibit NF-KB activity, and this transcription factor appears to be a critical component in the development of periprosthetic osteolysis by regulating the transcription of an exceptionally large number of genes [7,10,27,30,31,43]. In a previous study we demonstrated that titanium (Ti) particles could rapidly induce the chemotactic cytokine IL-8, an immediate early stress-responsive chemokine important for the activation and chemotaxis of neutrophils and macrophages [lo].…”

Section: Introductionmentioning

confidence: 99%

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Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-κB

et al. 2005

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Chemokines, or chemotactic cytokines, are major regulators of the inflammatory response and have been identified as pathogenic factors in the periprosthetic soft tissue. Particulate wear debris induced NF-KB activation, the major transcriptional regulator of IL-8 and MCP-1 pro-inflammatory genes and, indeed, both IL-8 and MCP-1 chemokine gene expressions were upregulated in titanium particulate-stimulated human osteoblasts. Here, we demonstrate that phagocytosed particles activate the IL-8 gene promQter via a NF-KB-mediated mechanism. Transfection of a dominant negative mutant IKBCX protein that cannot be serine phosphoryldted led to suppression of IL-8 promoter activity. The p651RelA NF-KB subunit activity was affected in both a time-and titanium particle concentration-dependent fashion. Titanium particles led to increased ERK, JNK, and p38 activation in MG-63 osteoblast cells, and IL-8 protein release was suppressed by specific inhibitors of the ERK and p38 MAPK pathways. Together, our results suggest that wear debris particles induce chemokine expression in osteoblasts via NF-KB-mediated transcriptional activation, which is controlled by the MAPK signal transduction pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Particlesmentioning

confidence: 99%

Section: Determination Of Nf-kb D N a Binding Activity And Nf-kb Subumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-κB

et al. 2005

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The role of fibroblasts and fibroblast‐derived factors in periprosthetic osteolysis

Koreny¹,

Tunyogi-Csapó²,

Gál³

et al. 2006

Arthritis & Rheumatism

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132

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Objective. This study was undertaken to investigate how fibroblasts respond to stimulation with particulate wear debris and/or conditioned media obtained from pathologic tissue, and whether these activated fibroblasts express compounds that are involved in bone resorption.Methods. Conditioned media from explant cultures of synovial tissue, periprosthetic soft tissue (interface membranes), titanium particles, and proinflammatory cytokines were used to stimulate fibroblasts. RNase protection assay was used to measure altered gene expression, and enzyme-linked immunosorbent assay, Western blot hybridization, and flow cytometry were used to determine fibroblast protein expression. Tartrate-resistant acid phosphatase staining was used to identify multinucleated osteoclast-like cells.Results. The most dominant compounds measured in the conditioned media from interface membranes were tumor necrosis factor ␣ (TNF␣), monocyte chemoattractant protein 1 (MCP-1), interleukin-1␤ (IL-1␤), IL-6, IL-8, and vascular endothelial growth factor. Fibroblasts phagocytosed particulate wear debris and responded to cytokine/chemokine stimulation. The most prominent up-regulated genes and proteins secreted by fibroblasts in response to stimulation were matrix metalloproteinase 1, MCP-1, IL-1␤, IL-6, IL-8, cyclooxygenase 1 (COX-1), COX-2, leukemia inhibitory factor 1, transforming growth factor ␤1 (TGF␤1), and TGF␤ receptor type I. In addition, interface membrane fibroblasts expressed RANKL and osteoprotegerin in response to stimulation with conditioned media, TNF␣, or IL-1␤. Stimulated fibroblasts cocultured with bone marrow cells in the presence of macrophage colonystimulating factor induced osteoclastogenesis.Conclusion. Interface membrane fibroblasts respond directly to particulate wear debris, possibly via phagocytosis, expressing proinflammatory cytokines and RANKL. Thus, these cells may be actively involved in osteoclastogenesis and pathologic (periprosthetic) bone resorption.

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Concentration‐ and composition‐dependent effects of metal ions on human MG‐63 osteoblasts

Hallab

Vermes

Messina

et al. 2002

J. Biomed. Mater. Res.

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255

146

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Metal debris from implants has been shown to alter the function of osteoblasts in cell cultures. Its remains unclear, however, if specific forms of released ionic metals are involved in the pathogenesis of periprosthetic osteolysis. We evaluated the relative effects of ionic forms of implant metals by treating human osteoblast-like MG-63 osteosarcoma cells with eight concentrations (0.001-10.0 mM) of Cr(+3), Mo(+5), Al(+3), Ta(+5), Co(+2), Ni(+2), Fe(+3), Cu(+2), Mn(+2), Mg(+2), Na(+2), and V(+3) chloride solutions. The results demonstrated that the metal ions differentially affected osteoblast proliferation, viability, type-I collagen gene expression, and cytokine release. The metal ions were ranked in order from least to most toxic (based on a 50% reduction in viability) as follows: Na < Cr < Mg < Mo < Al < Ta < Co < Ni < Fe < Cu < Mn < V. Metal-induced decreases in osteoblast proliferation were similar in ranking. Nontoxic concentrations of metals had no effect on procollagen alpha1[I] gene expression; only at toxic concentrations did metals produce a decrease in gene expression. The most toxic metals (V, Mn, Fe, and Ni) were also the only metals found to induce IL-6 secretion on a per cell basis (of the cytokines tested, interleukin 6 (IL-6), interleukin beta 1 (IL-1beta), transforming growth factor beta 1 (TGF-beta1), and tumor necrosis factor alpha (TNF-alpha), only IL-6 was detectable in the culture medium after 48 h for any metal at any concentration). Less toxic metals (e.g., Co and Cr) had little effect on IL-6 release, even at high concentrations. In general, metal ions reduced osteoblast function (i.e., proliferation and collagen gene expression) in proportion to the degree of toxicity. These results support the hypothesis that adverse local cellular responses (particularly necrotic responses) associated with metal debris from implanted metallic devices may be due in part to metal ions released from implants or from particulate debris.

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Down-Regulation of Procollagen α1[I] Messenger RNA by Titanium Particles Correlates with Nuclear Factor κB (NF-κB) Activation and Increased Rel A and NF-κB1 Binding to the Collagen Promoter

Abstract: Previously, we showed that exposure of human osteoblasts to titanium particles stimulates protein tyrosine phosphorylation (PTP), activates the transcription factor nuclear factor B (NF-B), and causes an approximately 50% decrease in the steady-state messenger RNA (

Cited by 35 publications

References 44 publications

Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-κB

Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-κB

The role of fibroblasts and fibroblast‐derived factors in periprosthetic osteolysis

Concentration‐ and composition‐dependent effects of metal ions on human MG‐63 osteoblasts

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