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 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.
Street
John
J
Department of Academic Surgery, National University of Ireland, University College Cork, Cork, Ireland.
Bao
Min
M
deGuzman
Leo
L
Bunting
Stuart
S
Peale
Franklin V
FV
Ferrara
Napoleone
N
Steinmetz
Hope
H
Hoeffel
John
J
Cleland
Jeffrey L
JL
Daugherty
Ann
A
van Bruggen
Nicholas
N
Redmond
H Paul
HP
Carano
Richard A D
RA
Filvaroff
Ellen H
EH
D000818:Animals; D001842:Bone and Bones / Q000098:blood supply / Q000293:injuries* / Q000378:metabolism*; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D005264:Femoral Fractures / Q000503:physiopathology*; D017102:Fracture Healing / Q000187:drug effects*; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D011884:Radius / Q000293:injuries; D013977:Tibia / Q000000981:diagnostic imaging / Q000293:injuries; D014057:Tomography, X-Ray Computed; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors