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Retroviral‐based gene therapy with cyclooxygenase‐2 promotes the union of bony callus tissues and accelerates fracture healing in the rat
Author(s) -
Rundle Charles H.,
Strong Donna D.,
Chen ShinTai,
Linkhart Thomas A.,
Sheng Matilda H.C.,
Wergedal Jon E.,
Lau K.H. William,
Baylink David J.
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1148
Subject(s) - bone healing , transgene , genetic enhancement , in vivo , biology , microbiology and biotechnology , gene , anatomy , biochemistry , genetics
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. Copyright © 2007 John Wiley & Sons, Ltd.