Cytokines and Osteolysis Around Total Hip Prostheses

Purpose: TNFa and IL-1 a are proinflammatory cytokines that are abundant in periprosthetic tissues. These cytokines stimulate bone resorption and have recently been shown to directly induce osteoclast formation in mouse marrow cultures. We examined whether TNFa and IL-la can directly induce osteoclast formation from human arthroplasty-derived (CD14') macrophages by a mechanism independent of RANKL-induced osteoclastogenesis.Methods; TNFa and M-CSF (HL-la) were added to cultures of magnetically sorted (CD14') and unsorted (CD14+/CD14-) cells isolated from the pseudomembrane of loosened hip arthroplasties. Osteoprotegerin (OPG), RANK:Fc and antibodies to TNF receptors (p55 and p75) were added to these cultures to distinguish the pathway of osteoclastogenesis. Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR) and lacunar resorption.Results: The addition of TNFa (HL-la) resulted in differentiation of CD14' macrophages into TRAP' and VNR' multinucleated cells capable of extensive lacunar resorption. Both OPG and RANK:Fc (which inhibit RANKL-induced osteoclastogenesis) did not block osteoclastogenesis. The addition of antibodies directed against the p55 receptor subunit of TNF resulted in significant inhibition of osteoclast formation and lacunar resorption.Conclusions: Our results indicate that, in the presence of M-CSF, TNFa is sufficient for inducing human osteoclast differentiation from arthroplasty macrophages and that TNFa acts synergistically with IL-la to stimulate lacunar resorption. This process is distinct from the RANWRANKL signalling pathway and is likely to operate in periprosthetic tissues when there is heavy wear particle deposition and cytokine production.

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“…TNFa, IL-laIP, IL-6) that stimulate local osteolysis [3,8,14,24,25,52]. In this study, we have shown that two of these cytokine factors, i.e.…”

Section: Discussionmentioning

confidence: 73%

Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis

Sabokbar

Kudo

Athanasou

2003

Journal Orthopaedic Research

119

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“…These data are interesting because one favored hypothesis concerning the pathogenesis of AL is that wear particles generated from the prosthesis stimulate phagocytosis by macrophages with the subsequent release of proinflammatory cytokines. [14][15][16] Ultra high molecular weight polyethylene (UHMWPE) has been widely used in total joint prosthesis, and UHMWPE components removed at revision surgery usually show evidence of wear. 17,18 Using our established mouse osteolysis model, we have demonstrated that UHMWPE particles provoke significant inflammation, osteoclastogenesis, and bone resorption.…”

Section: Introductionmentioning

confidence: 99%

Implant wear induces inflammation, but not osteoclastic bone resorption, in RANK^–/– mice

Ren

Peng

et al. 2006

Journal Orthopaedic Research

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Signaling of RANK (receptor activator of nuclear factor kappa B) through its ligand RANKL appears critical in osteolysis associated with aseptic loosening (AL). The purpose of this study was to investigate the role of RANK in a murine osteolysis model developed in RANK knockout (RANK À/À ) mice. Ultra high molecular weight polyethylene (UHMWPE) debris was introduced into established air pouches on RANK À/À mice, followed by implantation of calvaria bone from syngeneic littermates. Wild type C57BL/6 (RANK þ/þ ) mice injected with either UHMWPE or saline alone were included in this study. Pouch tissues were collected 14 days after UHMWPE inoculation for molecular and histology analysis. Results showed that UHMWPE stimulation induced strong pouch tissue inflammation in RANK À/À mice, as manifested by inflammatory cellular infiltration, pouch tissue proliferation, and increased gene expression of IL-1b, TNFa, and RANKL. However, the UHMWPE-induced inflammation in RANK À/À mice was not associated with the osteoclastic bone resorption observed in RANK þ/þ mice. In RANK þ/þ mice subjected to UHMWPE stimulation, a large number of TRAP þ cells were found on the implanted bone surface, where active osteoclastic bone resorption was observed. No TRAP þ cells were found in UHMWPE-containing pouch tissues of RANK À/À mice. Consistent with the lack of osteoclastic activity shown by TRAP staining, no significant UHMWPE particle-induced bone resorption was found in RANK À/À mice. A well preserved bone collagen content (Van Gieson staining) and normal plateau surface contour [microcomputed tomography (mCT)] of implanted bone was observed in RANK À/À mice subjected to UHMWPE stimulation. In conclusion, this study provides the evidence that UHMWPE particles induce strong inflammatory responses, but not associated with osteoclastic bone resorption in RANK À/À mice. This indicates that RANK signaling is essential for UHMWPE particle-induced osteoclastic bone resorption, but does not participate in UHMWPE particle-induced inflammatory response. ß

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“…In this model, macrophages in the periprosthetic environment express proinflammatory cytokines and enzymes in response to implant-derived wear particles. Both in vitro and in vivo evidence shows that wear debris-stimulated macrophages release interleukin-1 (IL-1) family and IL-6 cytokines, and these cytokines are found at high levels in osteolytic tissues (2)(3)(4)(5)(6), synovial fluid (7), and regional lymph nodes retrieved from failed THAs, while they are not found in stable implants (8). These cytokines are known to mediate bone resorption, both in vivo and in vitro.…”

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confidence: 99%

Polymorphisms in the interleukin‐1 receptor antagonist and interleukin‐6 genes affect risk of osteolysis in patients with total hip arthroplasty

Gordon¹,

Kiss-Tóth²,

Stockley³

et al. 2008

Arthritis & Rheumatism

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Objective. To determine whether osteolysis after total hip arthroplasty (THA) is associated with common polymorphisms within the genes encoding the interleukin-1 (IL-1) family and IL-6, and to determine whether polymorphisms that are associated with osteolysis affect in vitro messenger RNA (mRNA) expression in human peripheral blood mononuclear cells (PBMCs) in response to wear particles.Methods. Unrelated white subjects of North European descent (n ‫؍‬ 612) were recruited a mean of 11 years after cemented THA for primary osteoarthritis. Of these subjects, 272 had previous osteolysis and 340 had no radiographic evidence of osteolysis (control group). Genomic DNA was genotyped for the following singlenucleotide polymorphisms (SNPs): IL1A ؉4845, IL1B ؉3954, IL1B -3737, IL1B -511, IL1RA ؉2018, IL6 -174, IL6 -572, and IL6 -597. In a subset of 60 subjects, PBMCs were extracted and stimulated with titanium particles and/or endotoxin, and cytokine mRNA expression was measured using quantitative real-time reverse transcriptase-polymerase chain reaction.Results. The odds ratio (OR) for osteolysis associated with carriage of the IL1RA ؉2018C allele was 0.66 (95% confidence interval [95% CI] 0.48-0.91) (P ‫؍‬ 0.012). The remaining SNPs were not individually associated with osteolysis. The uncommon IL6 haplotype ؊174G/؊572G/؊597A (osteolysis group frequency 2.4%, control group frequency 0.8%) was associated with osteolysis (P ‫؍‬ 0.02, calculated using Haploview software). The IL1RA ؉2018CC genotype was associated with increased mRNA expression compared with the ؉2018TT genotype in both unstimulated and stimulated PBMCs (P ‫؍‬ 0.01 by analysis of variance, after Bonferroni correction).Conclusion. The IL1RA ؉2018C allele is associated with a decreased risk of osteolysis after THA and with increased IL-1 receptor antagonist mRNA expression in vitro. An uncommon haplotype within the promoter region of the gene for IL-6 is positively associated with osteolysis.

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Cytokines and Osteolysis Around Total Hip Prostheses

Cited by 110 publications

References 12 publications

Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis

Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis

Implant wear induces inflammation, but not osteoclastic bone resorption, in RANK^–/– mice

Polymorphisms in the interleukin‐1 receptor antagonist and interleukin‐6 genes affect risk of osteolysis in patients with total hip arthroplasty

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Cytokines and Osteolysis Around Total Hip Prostheses

Cited by 110 publications

References 12 publications

Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis

Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis

Implant wear induces inflammation, but not osteoclastic bone resorption, in RANK–/– mice

Polymorphisms in the interleukin‐1 receptor antagonist and interleukin‐6 genes affect risk of osteolysis in patients with total hip arthroplasty

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Implant wear induces inflammation, but not osteoclastic bone resorption, in RANK^–/– mice