Skeletal repair is a fundamental process that underlies many aspects of orthopaedic and musculoskeletal care ranging from fracture treatment to reconstructive surgery of the spine and extremities. Current estimates indicate that 5-10% of fractures experience delayed or impaired healing, 5-30% of spinal fusions fail to unite and the number of bone graft procedures performed worldwide exceeds 1.5 million per year. Thus while much has been learned regarding the biology of the bone repair process, significant gaps remain in our knowledge and a need exists for the development of strategies to enhance skeletal healing and regeneration. This application will cover areas of cell and molecular biology, biomedical engineering, and metabolic bone disease to provide a coordinated, integrated program of investigations on skeletal repair. Scientists with expertise in each of these domains will interact for the mutual gain of knowledge and synergistic development of concepts and ideas. The scientific program is composed of 3 projects and 4 cores. The projects will elucidate the mechanisms of angiogenesis in bone regeneration using a model of distraction osteogenesis, the role of BMPs in fracture healing using a novel transgenic model in which small-molecule-regulated protein dimerization is used to specifically activate a transcription factor that allows us to express noggin (an inhibitor of BMP function) or BMP2 in both in a conditional and tissue specific manner, and the effects of metabolic dysregulation on fracture healing using diabetes as a model system. The cores will provide services and databases to enhance the development of the projects. The genomics and informatics core will enhance the collection, organization and sharing of data among projects. A centralized facility for carrying out standardized measurements of skeletal healing will be established through the histomorphometry and biomechanics core. The cellular and molecular biology core will provide a centralized facility for the development and maintenance of the cellular and molecular biological reagents as well insure uniform quality control for all our surgical models. Finally, oversight and management of programmatic directives and funds and coordination of advisory input from the internal and external committees will be provided through the administrative core. The program intends to establish a more profound understanding of skeletal repair mechanisms through the integrative and collaborative activities of a team of investigators who have a track record of complimentary and synergistic scientific associations. Successful establishment and implementation of this program will greatly enhance the coordinated activities of this team of investigators and lead to important new results and directions for skeletal healing research.