Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2.
Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis during development, but little is known about the factors that control its expression. We provide the first example of tissue specific loss of VEGF expression as a result of targeting a single gene, Cbfa1/Runx2. During endochondral bone formation, invasion of blood vessels into cartilage is associated with upregulation of VEGF in hypertrophic chondrocytes and increased expression of VEGF receptors in the perichondrium. This upregulation is lacking in Cbfa1 deficient mice, and cartilage angiogenesis does not occur. Finally, over-expression of Cbfa1 in fibroblasts induces an increase in their VEGF mRNA level and protein production by stimulating VEGF transcription. The results demonstrate that Cbfa1 is a necessary component of a tissue specific genetic program that regulates VEGF during endochondral bone formation.
Zelzer
E
E
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Glotzer
D J
DJ
Hartmann
C
C
Thomas
D
D
Fukai
N
N
Soker
S
S
Olsen
B R
BR
D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000196:embryology* / Q000378:metabolism; D002356:Cartilage / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D017403:In Situ Hybridization; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins; D018919:Neovascularization, Physiologic; D010012:Osteogenesis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013977:Tibia / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D050659:Core Binding Factor Alpha 1 Subunit; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor