Retroviral-based gene therapy with cyclooxygenase-2 promotes the union of bony callus tissues and accelerates fracture healing in the rat.
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.
Rundle
Charles H
CH
Department of Medicine, Loma Linda University, Loma Linda, CA, USA.
Strong
Donna D
DD
Chen
Shin-Tai
ST
Linkhart
Thomas A
TA
Sheng
Matilda H-C
MH
Wergedal
Jon E
JE
Lau
K-H William
KH
Baylink
David J
DJ
D000818:Animals; D001483:Base Sequence; D002146:Bony Callus / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000096:biosynthesis; D005264:Femoral Fractures / Q000235:genetics / Q000628:therapy; D017102:Fracture Healing / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae / Q000235:genetics*; D019076:Transgenes
D051546:Cyclooxygenase 2; D015232:Dinoprostone