Vascular Endothelial Growth Factor Stimulates Bone Repair by Promoting Angiogenesis and Bone Turnover

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 repa...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-07, Vol.99 (15), p.9656-9661
Main Authors: Street, John, Bao, Min, deGuzman, Leo, Bunting, Stuart, Peale, Franklin V., Ferrara, Napoleone, Steinmetz, Hope, Hoeffel, John, Cleland, Jeffrey L., Daugherty, Ann, van Bruggen, Nicholas, Redmond, H. Paul, Richard A. D. Carano, Filvaroff, Ellen H.
Format: Article
Language:English
Subjects:
Angiogenesis
Animal models
Animals
Biological Sciences
Bone and Bones - blood supply
Bone and Bones - injuries
Bone and Bones - metabolism
Bone fractures
Bones
Callus
Cells, Cultured
Endothelial Growth Factors - pharmacology
Femoral fractures
Femoral Fractures - physiopathology
Femur
Fracture Healing - drug effects
Fractures
Healing
Humans
Immunology
Legs
Lymphokines - pharmacology
Male
Mice
Mice, Inbred C57BL
Neovascularization, Physiologic - drug effects
Osteoblasts
Osteoblasts - drug effects
Osteoblasts - physiology
Proteins
Rabbits
Radius - injuries
Tibia - diagnostic imaging
Tibia - injuries
Tomography, X-Ray Computed
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.152324099