Pseudoarthrosis (non-union) is a major complication of spine fusion. A novel approach for enhancing spine fusion and reducing the occurrence of pseudarthrosis is local gene therapy to up regulate the expression of an angiogenic growth factor. Angiogenesis is known to be critical in bone formation, remodeling of bone tissue and incorporation of bone graft. Furthermore various dysvascular states are associated with an increased incidence of pseudarthrosis after spine surgery. While a correlation between vascularity and successful fusion has been shown in clinical and experimental studies the precise role of enhancing angiogenesis as a potential therapeutic intervention for the enhancement of spine fusion has not previously been studied. In contrast to other recent gene therapy efforts in the area of spine fusion have focussed on the bone morphogenetic proteins (BMP's) and related genes such as LIM mineralization protein-1 (LMP-1), the investigations proposed here will focus on the use of the angiogenic vascular endothelial growth factor (VEGF) gene. VEGF is a particularly appropriate candidate gene for transfer to enhance spine fusion not only because of is ability to induce neo-angiogenesis, but because of the recently demonstrated importance of VEGF expression in osteogenesis, particularly bone mineralization. VEGF is a secreted protein growth factor which is a highly specific and potent mediator of angiogenesis. It is also a critical factor for ossification in the growth plate, where it supports both vascular invasion and chondroclast recruitment and/or differentiation. VEGF is up regulated in osteoblasts by bone morphogenetic protein-7 (BMP-7) as well as a number of other osteogenic growth factors (Yeh, Harada, Mehrara, Saadeh) and may be an essential downstream activity for these growth factors. Indeed BMP-7 has also been shown to be not only osteogenic but angiogenic possibly through the induction of VEGF (Ramoshebi). Previously, regional gene transfer using an adenovirus vector encoding VEGF (AdVEGF) has been shown to induce new blood vessel formation in both normoxic and hypoxic tissues (Mack, Magovern). Based on this knowledge we hypothesize that gene transfer and over expression by AdVEGF in the site of spine fusion will enhance bone formation in a rat model of posterolateral spine fusion. We have also previously shown in vivo bone formation by AdBMP-7 (Hidaka submitted). In this investigation, AdBMP-7-enhanced spine fusion will also be examined. Our hypothesis is that BMP-7-induced bone formation is dependent on VEGF expression.
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