Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover

J Street, M Bao, L deGuzman… - Proceedings of the …, 2002 - National Acad Sciences
J Street, M Bao, L deGuzman, S Bunting, FV Peale Jr, N Ferrara, H Steinmetz, J Hoeffel…
Proceedings of the National Academy of Sciences, 2002National Acad Sciences
Several growth factors are expressed in distinct temporal and spatial patterns during fracture
repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of
its ability to induce neovascularization (angiogenesis). To determine whether VEGF is
required for bone repair, we inhibited VEGF activity during secondary bone healing via a
cartilage intermediate (endochondral ossification) and during direct bone repair
(intramembranous ossification) in a novel mouse model. Treatment of mice with a soluble …
Several growth factors are expressed in distinct temporal and spatial patterns during fracture repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability to induce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, we inhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondral ossification) and during direct bone repair (intramembranous ossification) in a novel mouse model. Treatment of mice with a soluble, neutralizing VEGF receptor decreased angiogenesis, bone formation, and callus mineralization in femoral fractures. Inhibition of VEGF also dramatically inhibited healing of a tibial cortical bone defect, consistent with our discovery of a direct autocrine role for VEGF in osteoblast differentiation. In separate experiments, exogenous VEGF enhanced blood vessel formation, ossification, and new bone (callus) maturation in mouse femur fractures, and promoted bony bridging of a rabbit radius segmental gap defect. Our results at specific time points during the course of healing underscore the role of VEGF in endochondral vs. intramembranous ossification, as well as skeletal development vs. bone repair. The responses to exogenous VEGF observed in two distinct model systems and species indicate that a slow-release formulation of VEGF, applied locally at the site of bone damage, may prove to be an effective therapy to promote human bone repair.
National Acad Sciences