Vascular endothelial growth factor inhibits bone morphogenetic protein 2 expression in rat mesenchymal stem cells.
BACKGROUND
While several studies report that bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) can act synergistically to improve bone tissue engineering, others suggest that VEGF inhibits osteogenesis. The purpose of these experiments was therefore to evaluate the effect of dual transfection of these growth factors and potential mechanisms of interaction on gene expression and osteogenesis in vitro and in vivo.


METHODS
Marrow-derived mesenchymal stem cells (MSCs) were exposed to recombinant VEGF protein or transfected with adenoviruses encoding BMP2, VEGF, or LacZ in a variety of ratios. Alterations in gene and protein expression in vitro as well as bone formation in vivo were assessed.


RESULTS
MSC exposure to AdV-VEGF or recombinant VEGF inhibited BMP2 mRNA expression, protein production, and MSC differentiation. Coculture experiments revealed that BMP2 suppression occurs through both an autocrine and a paracrine mechanism, occurring at the transcriptional level. Compared to controls, cotransfection of VEGF and BMP2 transgenes prevented ectopic bone formation in vivo.


CONCLUSIONS
VEGF is a potent inhibitor of BMP2 expression in MSCs, and supplementation or overexpression of VEGF inhibits osteogenesis in vitro and ectopic bone formation in vivo. Strategies to utilize MSCs in bone tissue engineering therefore require careful optimization and precise delivery of growth factors for maximal bone formation.
Schönmeyr
Björn H
BH
Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Soares
Marc
M
Avraham
Tomer
T
Clavin
Nicholas W
NW
Gewalli
Fredrik
F
Mehrara
Babak J
BJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
D055396:Bone Morphogenetic Protein 2; D042461:Vascular Endothelial Growth Factor A