Gene therapy for osteoporosis: evaluation in a murine ovariectomy model

Baltzer, A. W. A.; Whalen, Janey D.; Wooley, Paul H.; Latterman, Christian; Truchan, L. M.; Robbins, Paul D.; Evans, Christopher H.

doi:10.1038/sj.gt.3301594

Cited by 51 publications

(27 citation statements)

References 42 publications

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“…Studies have shown that retroviral delivery of IL-1Ra was able to decrease inflammation and inflammatory cytokine production in a murine air pouch model of osteolysis (35). It has also been shown that IL-1Ra treatment diminishes the amount of bone loss in ovariectomized rats and mice (36, 37). Polymorphisms within the IL-1 gene cluster associated with increased IL-1Ra mRNA expression have also been associated with decreased susceptibility to osteolysis after total hip arthroplasty (38).…”

Section: Discussionmentioning

confidence: 99%

Periprosthetic osteolysis: Characterizing the innate immune response to titanium wear‐particles

Pierre

Chan

Iwakura

et al. 2010

Journal Orthopaedic Research

116

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Osteolysis of bone following total hip replacements is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone-resorption-inducing cytokine, interleukin 1β (IL-1β). NALP3, a NOD-like receptor protein located in the cytosol of macrophages, has been shown to signal the cleavage of pro-IL-1β into its mature, secreted form, IL-1β. Here we show that titanium particles stimulate the NALP3 inflammasome. We demonstrate that titanium induces IL-1β secretion from macrophages and this response is dependent on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase-1. We also show that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response is dependent on the expression of the IL-1 receptor and IL-1α/β. Moreover, administration of the IL-1 receptor antagonist (IL-1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle-induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL-1β secretion and IL-1-associated signaling, including neutrophil recruitment. Efficacy of IL-1Ra treatment introduces the potential for antagonist based-therapies for implant osteolysis.

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Section: Discussionmentioning

confidence: 99%

Periprosthetic osteolysis: Characterizing the innate immune response to titanium wear‐particles

Pierre

Chan

Iwakura

et al. 2010

Journal Orthopaedic Research

116

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“…It is interesting to note that PLGA-based NPs have also been proposed as gene carriers for gene therapy treatment of various disease models (Bivas-Benita et al, 2004;Zou et al, 2009;Liang et al, 2011). Gene therapy for osteoporosis treatment has been actively investigated by a number of research groups with promising results (Baltzer et al, 2001;Egermann et al, 2005;Zhang et al, 2012); therefore, it is anticipated that the success of our NP system may also serve as a novel non-viral gene delivery vehicle for osteoporosis treatment.…”

Section: Discussionmentioning

confidence: 99%

Poly aspartic acid peptide-linked PLGA based nanoscale particles: Potential for bone-targeting drug delivery applications

Jiang

Carbone

et al. 2014

International Journal of Pharmaceutics

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“…Although it is possible to deliver osteogenic genes to sites where secreted gene products are able to circulate systemically, such strategies are considered only for conditions such as osteoporosis, where there is disseminated loss of bone (Refs 34, 35, 36). There is some evidence that mesenchymal stem cells (MSCs) can home to fracture sites and deliver a genetic payload (Ref.…”

Section: Where To Transfer Genes?mentioning

confidence: 99%

Gene therapy for bone healing

Evans

2010

Expert Rev. Mol. Med.

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Clinical problems in bone healing include large segmental defects, nonunion and delayed union of fractures, and spinal fusions. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment.

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Gene therapy for osteoporosis: evaluation in a murine ovariectomy model

Cited by 51 publications

References 42 publications

Periprosthetic osteolysis: Characterizing the innate immune response to titanium wear‐particles

Periprosthetic osteolysis: Characterizing the innate immune response to titanium wear‐particles

Poly aspartic acid peptide-linked PLGA based nanoscale particles: Potential for bone-targeting drug delivery applications

Gene therapy for bone healing

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