Role of Angiogenesis in Bone Repair

Investigator: Theodore Miclau, MD
Sponsor: NIH National Institute Arthritis and Musculoskeletal and Skin Diseases

Location(s): United States


The candidate's objective is to conduct clinically relevant basic research as a clinician scientist. As an orthopaedic traumatologist, the long-term goal is to use the knowledge gained from basic research to improve fracture management. Over a 5 year period, the proposed work is intended to provide the tools to become an independent scientific investigator. His interests are in the molecular mechanisms that regulate skeletal repair. Impaired healing, occurring in approximately 560,000 fractures annually in the U.S., is physically disabling and costly. While the molecular and cellular events which occur during repair are poorly understood, there are clear similarities between adult bone healing and fetal bone formation. During development, angiogenesis is an essential, highly regulated process required for osteogenesis: in endochondral ossification, vessels penetrate the avascular hypertrophic cartilage, which then undergoes apoptosis and bone formation; and in intramembranous ossification, capillary formation is closely coordinated with the differentiation of osteoblasts from mesenchymal precursors, which form matrix and mineral. The hypothesis of this research proposal is that angiogenesis mediates the terminal differentiation of chondrocytes and osteoblasts during fracture repair. The aims of this research are: 1) to determine the spatial and temporal distribution of known angiogenic factors in adult bone repair using murine models which favor endochondral or intramembranous ossification; 2) to determine the extent to which ossification during healing is affected by angiogenesis; and 3) to explore the relation of the determinants of cartilage maturation, cartilage differentiation, and hypertrophic cartilage degradation, to the angiogenic program. The training will include necessary didactic studies in cellular and molecular biology, biochemistry, statistics and the responsible conduct of science.