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Mechanisms of Fibroblast Growth Factor-2 Modulation of Vascular Endothelial Growth Factor Expression by Osteoblastic Cells

Laboratory of Developmental Biology and Repair, Department of Surgery, New York University School of Medicine, New York, New York 10016; Department of Surgery, University of Connecticut (P.B.S.), Farmington, Connecticut 06032; Department of Surgery, New York University (B.J.M., D.S.S., J.A.S., J.A.G., G.S.C., G.K.G., M.T.L.), New York, New York 10016; and Department of Cardiology, Kyushu University School of Medicine (H.U.), Fukuoka 812, Japan

Address all correspondence and requests for reprints to: Michael T. Longaker, M.D., Laboratory of Developmental Biology and Repair, Room H-169, New York University Medical Center, 550 First Avenue, New York, New York 10016. E-mail: michael.longaker{at}med.nyu.edu

Normal bone growth and repair is dependent on angiogenesis. Fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), and transforming growth factor-ß (TGFß) have all been implicated in the related processes of angiogenesis, growth, development, and repair. The purpose of this study was to investigate the relationships between FGF-2 and both VEGF and TGFß in nonimmortalized and clonal osteoblastic cells. Northern blot analysis revealed 6-fold peak increases in VEGF mRNA at 6 h in fetal rat calvarial cells and MC3T3-E1 osteoblastic cells after stimulation with FGF-2. Actinomycin D inhibited these increases in VEGF mRNA, whereas cycloheximide did not. The stability of VEGF mRNA was not increased after FGF-2 treatment. Furthermore, FGF-2 induced dose-dependent increases in VEGF protein levels (P < 0.01). Although in MC3T3-E1 cells, TGFß1 stimulates a 6-fold peak increase in VEGF mRNA after 3 h of stimulation, we found that both TGFß2 and TGFß3 yielded 2- to 3-fold peak increases in VEGF mRNA levels noted after 6 h of stimulation. Similarly, both TGFß2 and TGFß3 dose dependently increased VEGF protein production. To determine whether FGF-2-induced increases in VEGF mRNA may have occurred independently of TGFß, we disrupted TGFß signal transduction (using adenovirus encoding a truncated form of TGFß receptor II), which attenuated TGFß1 induction of VEGF mRNA, but did not impede FGF-2 induction of VEGF mRNA. In summary, FGF-2-induced VEGF expression by osteoblastic cells is a dose-dependent event that may be independent of concomitant FGF-2-induced modulation of TGFß activity.

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