Wear Debris Inhibition of Anti-Osteoclastogenic Signaling by Interleukin-6 and Interferon- : Mechanistic Insights and Implications for Periprosthetic Osteolysis

Rakshit, Diptendu S.; Ly, Khanh; Sengupta, Tapas K.; Nestor, Bryan J.; Sculco, Thomas P.; Ivashkiv, Lionel B.; Purdue, P. Edward

doi:10.2106/jbjs.e.00711

Cited by 62 publications

(86 citation statements)

References 42 publications

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“…RNA was further purified using RNeasy Mini columns and DNAse I digestion (QIAGEN Inc., Valencia, CA) to remove any contaminating DNA, and subjected to real-time quantitative PCR in triplicate as described previously. 21 All primer pairs (listed in Table 2) spanned at least one intron to avoid any possibility of contaminating signals arising from trace amounts of contaminating genomic DNA. For each gene, generation of the correct PCR product was confirmed by melting curve analysis, and fold difference in the abundance of mRNA (compared to the housekeeping gene HPRT) was then calculated using the d-d Ct method 35 with the assumption of ideal primer efficiencies.…”

Section: Tissue Collectionmentioning

confidence: 99%

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

Koulouvaris

Ivashkiv

et al. 2007

Journal Orthopaedic Research

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Interactions between periprosthetic cells and prosthetic wear debris have been recognized as an important event in the development of osteolysis and aseptic loosening. Although the ability of wear debris to activate pro-inflammatory macrophage signaling has been documented, the full repertoire of macrophage responses to wear particles has not been established. Here, we examined the involvement of alternative macrophage activation and defective osteogenic signaling in osteolysis. Using real-time RT-PCR analysis of periprosthetic soft tissue from osteolysis patients, we detected elevated levels of expression of alternative macrophage activation markers (CHIT1, CCL18), chemokines (IL8, MIP1 a) and markers of osteoclast precursor cell differentiation and multinucleation (Cathepsin K, TRAP, DC-STAMP) relative to osteoarthritis controls. The presence of cathepsin K positive multinuclear cells was confirmed by immunohistochemistry. Reduced expression levels of the osteogenic signaling components BMP4 and FGF18 were detected. Expression levels of TNF-a, IL-6, and RANKL were unchanged, while the anti-osteoclastogenic cytokine OPG was reduced in osteolysis patients, resulting in elevated RANKL:OPG ratios. In vitro studies confirmed the role of particulate debris in alternative macrophage activation and inhibition of osteogenic signaling. Taken together, these results suggest involvement in osteolysis of alternative macrophage activation, accompanied by elevated levels of various chemokines. Increased recruitment and maturation of osteoclast precursors is also observed, as is reduced osteogenesis. These findings provide new insights into the molecular pathogenesis of osteolysis, and identify new potential candidate markers for disease progression and therapeutic targeting. ß

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Section: Tissue Collectionmentioning

confidence: 99%

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

Koulouvaris

Ivashkiv

et al. 2007

Journal Orthopaedic Research

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“…Other cells of potential interest in the pathology of debris-induced osteolysis include osteoclasts [28,58,60], osteoblasts [71], lymphocytes [7], and mesenchymal cells [62].…”

Section: Search Strategy and Criteriamentioning

confidence: 99%

How Has the Introduction of New Bearing Surfaces Altered the Biological Reactions to Byproducts of Wear and Modularity?

Wooley

2014

Clin Orthop Relat Res

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Background Biological responses to wear debris were largely elucidated in studies focused on conventional ultrahigh-molecular-weight polyethylene (UHMWPE) and some investigations of polymethymethacrylate cement and orthopaedic metals. However, newer bearing couples, in particular metal-on-metal but also ceramic-on-ceramic bearings, may induce different biological reactions. Questions/purposes Does wear debris from the newer bearing surfaces result in different biological responses compared with the known responses observed with conventional metal-on-UHMWPE bearings?Methods A Medline search of articles published after 1996 supplemented by a hand search of reference lists of included studies and relevant conference proceedings was conducted to identify the biological responses to orthopaedic wear debris with a focus on biological responses to wear generated from metal-on-highly crosslinked polyethylene, metal-on-metal, ceramic-on-ceramic, and ceramicon-polyethylene bearings. Articles were selected using criteria designed to identify reports of wear debris particles and biological responses contributing to prosthesis failure. Case reports and articles focused on either clinical outcomes or tribology were excluded. A total of 83 papers met the criteria and were reviewed in detail.

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“…But is this the only way in which wear debris may act upon OCPs? Recent studies in our laboratory question whether, in addition to stimulating inflammatory RANKL expression within periprosthetic tissues, wear debris might also act directly upon OCPs, to modulate signaling pathways and responses to cytokines within these cells, and hence impact their differentiation and/or activation [68].…”

Section: Oc Generation and Activationmentioning

confidence: 99%

“…For instance, PMMA bone cement and titanium can each, within 15-30 min, induce activation by phosphorylation of all three of the major MAP kinase subgroups, namely, p38, ERK, and JNK [68]. These three pathways are involved in numerous cellular activities, and all three are required for osteoclast generation and activation [113].…”

Section: Map Kinasesmentioning

confidence: 99%

“…These three pathways are involved in numerous cellular activities, and all three are required for osteoclast generation and activation [113]. Inhibition of MAP kinase activation reduces the ability of wear debris to induce proinflammatory cytokine induction in cultured OCPs [68], suggesting that MAP kinases are critical transducers of the signals emanating from particle-cell interaction to the nucleus. There appears to be considerable redundancy among the different MAP kinase families in this respect, because inhibition of multiple MAP kinase subgroups is far more effective in down-regulating particle action than inhibition of any single subgroup alone.…”

Section: Map Kinasesmentioning

confidence: 99%

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The Central Role of Wear Debris in Periprosthetic Osteolysis

Purdue

Koulouvaris

Nestor

et al. 2006

HSS Journal®: The Musculoskeletal Journal of Hospital for Speci

217

190

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Periprosthetic osteolysis remains the leading complication of total hip arthroplasty, often resulting in aseptic loosening of the implant, and a requirement for revision surgery. Wear-generated particular debris is the main cause of initiating this destructive process. The purpose of this article is to review recent advances in our understanding of how wear debris causes osteolysis, and emergent strategies for the avoidance and treatment of this disease. The most important cellular target for wear debris is the macrophage, which responds to particle challenge in two distinct ways, both of which contribute to increased bone resorption. First, it is well known that wear debris activates proinflammatory signaling, which leads to increased osteoclast recruitment and activation. More recently, it has been established that wear also inhibits the protective actions of antiosteoclastogenic cytokines such as interferon gamma, thus promoting differentiation of macrophages to bone-resorbing osteoclasts. Osteoblasts, fibroblasts, and possibly lymphocytes may also be involved in responses to wear. At a molecular level, wear particles activate MAP kinase cascades, NF.B and other transcription factors, and induce expression of suppressors of cytokine signaling. Strategies to reduce osteolysis by choosing bearing surface materials with reduced wear properties (such as metal-on-metal) should be balanced by awareness that reducing particle size may increase biological activity. Finally, although therapeutic agents against proinflammatory mediators [such as tumor necrosis factor (TNF)] and osteoclasts (bisphosphonates and molecules blocking RANKL signaling) have shown promise in animal models, no approved treatments are yet available to osteolysis patients. Considerable efforts are underway to develop such therapies, and to identify novel targets for therapeutic intervention.

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Wear Debris Inhibition of Anti-Osteoclastogenic Signaling by Interleukin-6 and Interferon- : Mechanistic Insights and Implications for Periprosthetic Osteolysis

Cited by 62 publications

References 42 publications

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

How Has the Introduction of New Bearing Surfaces Altered the Biological Reactions to Byproducts of Wear and Modularity?

The Central Role of Wear Debris in Periprosthetic Osteolysis

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