Retroviral-based gene therapy with cyclooxygenase-2 promotes the union of bony callus tissues and accelerates fracture healing in the rat |
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Authors: | Rundle Charles H Strong Donna D Chen Shin-Tai Linkhart Thomas A Sheng Matilda H-C Wergedal Jon E Lau K-H William Baylink David J |
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Institution: | Department of Medicine, Loma Linda University, Loma Linda, CA, USA. |
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Abstract: | BACKGROUND: An in vivo gene therapy strategy was developed to accelerate bone fracture repair. METHODS: Direct injection of a murine leukemia virus-based vector targeted transgene expression to the proliferating periosteal cells arising shortly after fracture. Cyclooxygenase-2 (Cox-2) was selected because the transgene for its prostaglandin products that promote angiogenesis, bone formation and bone resorption, are all required for fracture healing. The human (h) Cox-2 transgene was modified to remove AU-rich elements in the 3'-untranslated region and to improve protein translation. RESULTS: In vitro studies revealed robust and sustained Cox-2 protein expression, prostaglandin E(2) and alkaline phosphatase production in rat bone marrow stromal cells and osteoblasts transgenic for the hCox-2 gene. In vivo studies in the rat femur fracture revealed that Cox-2 transgene expression produced bony union of the fracture by 21 days post-fracture, a time when cartilage persisted within the fracture tissues of control animals and approximately 1 week earlier than the healing normally observed in this model. None of the ectopic bone formation associated with bone morphogenetic protein gene therapy was observed. CONCLUSIONS: This study represents the first demonstration that a single local application of a retroviral vector expressing a single osteoinductive transgene consistently accelerated fracture repair. |
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Keywords: | bone cyclooxygenase‐2 fracture healing gene therapy prostagland‐ ins retroviral vectors |
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