Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis

Yang, Shang-You; Wu, Bin; Mayton, Lois; Mukherjee, Pinku; Robbins, Paul D.; Evans, Christopher H.; Wooley, Paul H.

doi:10.1038/sj.gt.3302192

Cited by 73 publications

(79 citation statements)

References 51 publications

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“…It is still unknown whether an inhibitory effect of EM on inflammatory osteoclastogenesis is through a direct effect or indirectly through the reduction of pro-inflammatory cytokines and tissue inflammation. 4,20 As reported previously, 19 implanted bone degradation is often located at areas in close contact with UHMWPE particle-stimulated inflammatory membranes, with the invasion front formed mainly by macrophage/osteoclasts, associated with bone collagen depletion at the bone surface. As a result of diminished inflammatory osteoclastogenesis, EM treatment dramatically attenuated bone resorption, manifested by undetectable bone erosion and less bone collagen depletion, compared with untreated mice.…”

Section: Discussionmentioning

confidence: 83%

“…19 This model demonstrates a rapid and reproducible method to evaluate wear debris-induced osteolysis, and provides a useful tool to screen anti bone resorption compounds and other therapeutic approaches. 14,20 In the present study, we have used this model to investigate the effect of EM on UHMWPE particles-induced inflammatory osteolysis in vivo, and have demonstrated that EM inhibits UHMPWE particles-induced inflammation, osteoclastogenesis, and bone resorption.…”

Section: Introductionmentioning

confidence: 99%

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Erythromycin inhibits wear debris‐induced inflammatory osteolysis in a murine model

Ren

Peng

et al. 2005

Journal Orthopaedic Research

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Up to 20% of patients with total joint arthroplasty will develop radiographic evidence of aseptic loosening (AL), which most likely results from an inflammatory response to billions of wear debris shed from the implant. Our previous work has demonstrated that erythromycin (EM), a macrolide antibiotic, inhibits wear debris-induced inflammatory osteoclastogenesis through the reduction of cytokine production and osteoclast differentiation, both of which involve the NF-kB pathway. The aim of the current study was to determine whether EM inhibits wear debris-induced inflammatory osteolysis in a murine osteolysis model. Ultrahigh molecular-weight polyethylene (UHMWPE) debris was introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. EM (2 mg/kg/day) was given to mice intraperitoneally 2 days before UHMWPE introduction and maintained until the sacrifice of the mice. Mice with and without EM treatment, as well as control mice injected with saline alone were included in this study. Pouch tissues were collected 14 days after UHMWPE inoculation for molecular and histology analysis. Our findings indicate that: (1) EM reduced UHMWPE-induced tissue inflammation, including the diminished pouch membrane thickness, reduced inflammatory cellular infiltration, and lowered IL-1b and TNF-a expression (mRNA and protein); (2) EM inhibited UHMWPE-induced osteoclastogenesis, with reduced gene activation of RANK, RANKL, and CPK, and diminished RANKL expression in UHMWPE stimulated pouches, and (3) EM markedly reduced the number of TRAP þ cells in pouch tissues, and protected against bone collagen depletion. In conclusion, this study provides the evidence that EM inhibits the UHMWPE particles-induced inflammatory osteolysis in a murine model, and represents a promising therapeutic candidate for the prevention and treatment of AL. ß

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Erythromycin inhibits wear debris‐induced inflammatory osteolysis in a murine model

Ren

Peng

et al. 2005

Journal Orthopaedic Research

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“…In the second model, osteolysis is studied in bones implanted into air pouches, which therefore lack a blood supply and are more analogous to bone organ culture experiments rather than to the in vivo situation [45,46]. Moreover, the extent of bone loss induced by particles in the air pouch model has not been described [45,46].…”

Section: Introductionmentioning

confidence: 99%

Polyethylene and titanium particles induce osteolysis by similar, lymphocyte‐independent, mechanisms

Taki¹,

Tatro²,

Nalepka³

et al. 2005

Journal Orthopaedic Research

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Periprosthetic osteolysis is a major clinical problem that limits the long-term survival of total joint arthroplasties. Osteolysis is induced by implant-derived wear particles, primarily from the polyethylene bearing surfaces. This study examined two hypotheses. First, that similar mechanisms are responsible for osteolysis induced by polyethylene and titanium particles. Second, that lymphocytes do not play a major role in particle-induced osteolysis. To test these hypotheses, we used the murine calvarial model that we have previously used to examine titanium-induced osteolysis. Polyethylene particles rapidly induced osteolysis in the murine calvaria 5-7days after implantation. The polyethylene-induced osteolysis was associated with large numbers of osteoclasts as well as the formation of a thick periosteal fibrous tissue layer with numerous macrophages containing phagocytosed polyethylene particles. Polyethylene-induced osteolysis was rapidly repaired and was undetectable by day 21 after implantation. Lymphocytes were noted in the fibrous layer of wild-type mice. However, the amount of osteolysis and cytokine production induced by polyethylene particles was not substantially affected by the lack of lymphocytes in PfplRag2 double knock out mice. All of these findings are similar to our observations of osteolysis induced by titanium particles. These results provide strong support for both of our hypotheses: that similar mechanisms are responsible for osteolysis induced by polyethylene and titanium particles and that lymphocytes do not play a major role in particle-induced osteolysis.

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“…It is upregulated in aseptic loosening [4,6,7,15,16] and by wear particles in vitro [1][2][3] and in vivo [8,9]. Blockage of IL-1 activity inhibits particle-induced inflammation and osteoclast differentiation, respectively, in the murine femoral and air pouch models [17,18]. Moreover, a polymorphism in the gene that encodes the IL-1 receptor antagonist is also associated with an increased frequency of aseptic loosening [19].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the roles of IL-1, IL-6, and TNFα in cell culture and murine models of aseptic loosening

Taki

Tatro

Lowe

et al. 2007

Bone

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Pro-inflammatory cytokines, such as IL-1, IL-6, and TNF, are considered to be major mediators of osteolysis and ultimately aseptic loosening. This study demonstrated that synergistic interactions among these cytokines are required for the in vitro stimulation of osteoclast differentiation by titanium particles. In contrast, genetic knock out of these cytokines or their receptors does not protect murine calvaria from osteolysis induced by titanium particles. Thus, the extent of osteolysis was not substantially altered in single knock out mice lacking either the IL-1 receptor or IL-6. Osteolysis also was not substantially altered in double knock out mice lacking both the IL-1 receptor and IL-6 or in double knock out mice lacking both TNF receptor-1 and TNF receptor-2. The differences between the in vivo and the cell culture results make it difficult to conclude whether the pro-inflammatory cytokines contribute to aseptic loosening. One alternative is that in vivo experiments are more physiological and that therefore the current results do not support a role for the pro-inflammatory cytokines in aseptic loosening. We however favor the alternative that, in this case, the cell culture experiments can be more informative. We favor this alternative because the role of the proinflammatory cytokines may be obscured in vivo by compensation by other cytokines or by the low signal to noise ratio found in measurements of particle-induced osteolysis.

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Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis

Cited by 73 publications

References 51 publications

Erythromycin inhibits wear debris‐induced inflammatory osteolysis in a murine model

Erythromycin inhibits wear debris‐induced inflammatory osteolysis in a murine model

Polyethylene and titanium particles induce osteolysis by similar, lymphocyte‐independent, mechanisms

Comparison of the roles of IL-1, IL-6, and TNFα in cell culture and murine models of aseptic loosening

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