A novel murine model of orthopaedic wear‐debris associated osteolysis

Ren, Wei; Yang, Shang-You; Ph, Wooley

doi:10.1080/03009740410005944

Cited by 43 publications

(71 citation statements)

References 26 publications

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“…Our data support recent findings that the NF-KB signalling pathway may be involved in wear particleinduced periprosthetic osteolysis [16,18,35,41,45]. Our study extends these results and shows for the first time that not only TiAlV-, mixed-, or PMMA-particles [35,40], but also polyethylene-particles induce an activation of NF-KB signalling and the TNFa-promoter.…”

Section: Discussionsupporting

confidence: 92%

“…These findings are complementary to the transfection assay study by Merkel et al [35] showing that PMMA-particles induce activation of TNFa promoter almost 5-fold. Several studies [19,36,41,45] have shown that titanium alloy-, mixed-and PMMA-particles activate NF-KB using electrophoretic mobility assays (EMSA). These studies include a methodical limitation because EMSAs do not provide a basis for quantitative and functional analysis of factors that potentially regulate gene expression.…”

Section: Discussionmentioning

confidence: 99%

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Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

et al. 2005

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Wear particles are believed to induce periprosthetic inflammation which contributes to periprosthetic osteolysis. TNFu plays a pivotal role in the pathogenesis of this process. The molecular mechanisms leading to the development of periprosthetic inflammation with upregulated TNFa expression in monocytic cells in response to different wear particles have yet to be defined. 1n:this study we evaluated the effects of polyethylene-and TiAIV-particles on activation of NF-KB signalling pathways and TNFa biosynthesis and release in monocytic cells with respect to periprosthetic osteoclastogenesis. THP-1 monocytic cells were differentiated to macrophage-like cells and exposed to LPS-detoxified polyethylene and prosthesis-derived TiAlV-particles. TNFa release was analyzed in culture supernatant by ELISA. NF-KB activation was examined by electrophoretic mobility shift assay (EMSA), and NF-KB target promoter activities including transactivation of the TNFa promoter were determined by luciferase reporter gene assays. Differentiated THP-1 macrophages were exposed to increasing numbers of particles for 0, 60, 180 and 360 min. Both, polyethylene-and TiAIV-particles induced a significant activation of both NF-KB and TNFa promoters at 180 min. A significant TNFu release was detected after 360 min exposure to polyethylene-and TiAlV-particles in a dose dependent manner. In comparison, LPS induced a much greater activation of NF-KB and TNFa promoters, and TNFa secretion into the supernatant was strongly induced. These results provide evidence that induction of the NF-KB signal transduction pathway in macrophages plays a major role in initiating and mediating the inflammatory response leading to periprosthetic osteolysis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

et al. 2005

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“…The use of the bone implanted inflammatory air pouch as a model of debris-induced osteolysis has been described previously. 19 Air pouches were established by subcutaneous injection of sterile air on the back of C57BL/6 mice of either RANK þ/þ or RANK À/À phenotype (the generous gift of Amgen Inc., Seattle, WA). Each experimental group consisted of 10 mice.…”

Section: Mouse Osteolysis Modelmentioning

confidence: 99%

“…Paraffin sections (6 mm) were stained with hematoxylin & eosin (H&E) and the microscopic digital images photographed and analyzed as described previously. 19,22 Modified naphthol AS-D chloroacetate esterase staining was used to detect monocytes/macrophages. Osteoclast formation was determined by tartrate-resistant acid phosphatase (TRAP, EC3.1.3.2) staining in paraffin tissue sections (6 mm) using a commercial kit (Sigma, St. Louis, MO), as described previously.…”

Section: Histological Assessmentmentioning

confidence: 99%

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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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Adeno‐associated virus–mediated osteoprotegerin gene transfer protects against particulate polyethylene–induced osteolysis in a murine model

Yang

Mayton

et al. 2002

Arthritis & Rheumatism

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Objective. Osteoprotegerin (OPG), a natural negative regulator of osteoclastogenesis and bone resorption, may be a potential therapeutic agent for treatment of osteolysis-associated prosthetic joint loosening. Using an in vivo adeno-associated virus (AAV)-mediated gene transfer technique, this study was designed to evaluate the protective effects of OPG transgene against orthopedic wear debris-induced bone loss in a murine model of osteolysis.Methods. Bone tissue was implanted into established pouches on BALB/c mice, followed by the introduction of ultra-high-molecular-weight polyethylene (UHMWPE) particles to provoke inflammation and osteolysis. The viruses encoding human OPG gene (rAAV-hOPG) or ␤-galactosidase marker gene (rAAVLacZ) were injected into the air pouches, and the tissue was harvested 7 days after viral infection for histologic and molecular analyses.Results. Successful transgene expression was confirmed by the detection of OPG by enzyme-linked immunosorbent assay and positive X-Gal staining of pouch tissue (LacZ). Real-time polymerase chain reaction indicated significant diminishment of messenger RNA expression of osteoclast markers in OPGtransduced pouches compared with rAAV-LacZtransduced pouches. The transduction and expression of OPG also markedly decreased the gene copies of the biologic receptor activator of nuclear factor B. The expression of OPG in the bone-implanted pouch reduced bone calcium release by a mean of 39% compared with the calcium release in the other 2 groups. Computerized image analysis revealed that expression of OPG significantly protected against bone collagen loss.Conclusion. OPG gene transfer mediated by rAAV effectively protects against particulate polyethyleneinduced bone resorption in this experimental model. Data suggest that gene transfer using rAAV-OPG may be a feasible and effective therapeutic candidate to treat or prevent wear debris-associated osteolysis and aseptic loosening.

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A novel murine model of orthopaedic wear‐debris associated osteolysis

Abstract: This model demonstrates a sensitive, rapid, and reproducible method for studying wear-debris induced osteolysis seen in patients with aseptic loosening.

Cited by 43 publications

References 26 publications

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

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

Adeno‐associated virus–mediated osteoprotegerin gene transfer protects against particulate polyethylene–induced osteolysis in a murine model

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A novel murine model of orthopaedic wear‐debris associated osteolysis

Abstract: This model demonstrates a sensitive, rapid, and reproducible method for studying wear-debris induced osteolysis seen in patients with aseptic loosening.

Cited by 43 publications

References 26 publications

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

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

Adeno‐associated virus–mediated osteoprotegerin gene transfer protects against particulate polyethylene–induced osteolysis in a murine model

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