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

Yang, Shang-You; Mayton, Lois; Wu, Bin; Goater, J. Jeffrey; Schwarz, Edward M.; Wooley, Paul H.

doi:10.1002/art.10527

Cited by 77 publications

(74 citation statements)

References 34 publications

(39 reference statements)

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“…We demonstrated that an in vivo viralmediated gene transfer of osteoprotegerin (OPG), a secreted TNF receptor-related protein that neutralizes RANKL bioactivity, 6 exerted protective effects against wear debris-induced inflammatory osteolysis. 14 In this study, we utilize the same animal model to demonstrate that EM inhibits wear particle-induced osteoclastogenesis. The study generated two additional findings.…”

Section: Discussionmentioning

confidence: 99%

“…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: 89%

“…3,6,8,11 Using a mouse inflammation model, 12 we have demonstrated that ultrahigh molecular-weight polyethylene (UHMWPE) debris provokes tissue inflammation associated with a significant increase of RANKL gene expression. 4 In fact, blocking RANKL activity using either an antagonist RANK:Fc IgG 13 or an adeno-associated virus (AAV)-mediated OPG gene therapy 14 inhibit wear debris-stimulated osteoclast formation and bone resorption. These data indicate the potential of a treatment strategy targeted towards the RANK/ RANKL pathway.…”

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: 99%

Section: Introductionmentioning

confidence: 89%

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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“…With this strategy, it has been proposed to use OPG in order to decrease the bone resorption when particles are present [42,43]. The delivery of OPG could be done through gene therapy [44] or could be locally delivered as it has been recently proposed to use the orthopedic implant as drug delivery system [45].…”

Section: Article In Pressmentioning

confidence: 99%

The influence of wear particles in the expression of osteoclastogenesis factors by osteoblasts

Pioletti

Kottelat

2004

Biomaterials

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Orthopedic implant failures are often associated with peri-implant osteolysis. Particles generated from the wear process have been suspected to play an important role in this situation. Indeed, the peri-implant osteolysis could be due to the presence of particles stimulating the osteoclastogenesis process. We hypothesize then that the presence of a low particle concentration positively influences osteoblasts to produce osteoclastogenesis factors. If true, this hypothesis would then support the idea that the particles could be at the origin of the process leading to implant loosening. To check the validity of this hypothesis, we quantified in vitro the production of different genes involved in the osteoclastogenesis process using primary isolated human osteoblasts treated or not with particles. Results showed that low concentrations of particles might have a stimulating effect on osteoblasts to produce osteoclastogenesis factors as demonstrated by the increase of RANKL and CSF-1 gene expression in the particle group. r

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

Cited by 77 publications

References 34 publications

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

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

The influence of wear particles in the expression of osteoclastogenesis factors by osteoblasts

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

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