The treatment and correction of dentoalveolar malocclusions and osseous craniofacial abnormalities is based primarily on the application of mechanically-generated forces. During orthodontic and ortho-surgical treatments, mechanical transport is routinely used for the correction of tooth position within the bone and for expansion of palatal width to accommodate new tooth growth and discrepancies in jaw length. The latter form of bone induction and remodeling is nearly identical to those found in classical applications of distraction osteogenesis used for limb lengthening. While these procedures are extensively used clinically, the basic mechanisms by which they promote new bone formation are not well understood. One of the primary features of these procedures that generate bone by distraction is that they are primarily intramembranous processes devoid of extensive amounts of cartilage. An observed histological feature of these processes of bone regeneration is the observation of robust vascularization of the repair tissue both proceeding and continuing to be present during the regeneration process. The hypothesis of this proposal is that bone regeneration during distraction osteogenesis is driven by signals derived from the angiogenic process. In order to test this hypothesis and develop genetic models to examine the molecular mechanisms that regulate bone formation we have developed a murine model of distraction osteogenesis. In initial studies we will define the temporal and spatial expression of the angiogenic and bone morphogenetic signals that drive new bone formation during distraction osteogenesis. In subsequent experiments we will specifically block VEGF mediated angiogenesis using blocking antibodies to this angiogenic factor, and functionally test if this gene is a primary mediator of angiogenesis during distraction osteogenesis and if blocking its activity effects ossification. These experiments represent the first steps in defining the molecular mechanisms that regulate bone formation during distraction osteogenesis and test the functional role of angiogenic regulators in this process.
