Abstract
It is recognized that Wnt3a affects bone metabolism via the canonical Wnt/β-catenin signalling pathway. We have previously shown that transforming growth factor-β (TGF-β) stimulates the synthesis of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and p38 MAP kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of Wnt3a on TGF-β-stimulated VEGF synthesis in these cells. Wnt3a, which alone had little effect on the VEGF levels, significantly enhanced the TGF-β-stimulated VEGF release. Lithium chloride and SB216763, inhibitors of glycogen synthase kinase 3β, markedly amplified the TGF-β-stimulated VEGF release. Wnt3a failed to affect the TGF-β-induced phosphorylation of Smad2, p44/p42 MAP kinase, p38 MAP kinase or SAPK/JNK. Wnt3a and lithium chloride strengthened the VEGF mRNA expression induced by TGF-β. These results strongly suggest that Wnt3a upregulates VEGF synthesis stimulated by TGF-β via activation of the canonical pathway in osteoblasts.
Copyright © 2011 John Wiley & Sons, Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Enzyme Inhibitors / pharmacology
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Indoles / pharmacology
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Lithium Chloride / pharmacology
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MAP Kinase Kinase 4 / drug effects
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MAP Kinase Kinase 4 / metabolism
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Maleimides / pharmacology
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Mice
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism
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Osteoblasts / drug effects
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Osteoblasts / metabolism*
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Phosphorylation / drug effects
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RNA, Messenger
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Signal Transduction
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Smad2 Protein / drug effects
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Smad2 Protein / metabolism
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology
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Up-Regulation
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Vascular Endothelial Growth Factor A / biosynthesis*
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Vascular Endothelial Growth Factor A / drug effects
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Vascular Endothelial Growth Factor A / genetics
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Wnt Proteins / metabolism*
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Wnt Proteins / pharmacology
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Wnt3 Protein
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Wnt3A Protein
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beta Catenin / metabolism
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p38 Mitogen-Activated Protein Kinases / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Enzyme Inhibitors
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Indoles
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Maleimides
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RNA, Messenger
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SB 216763
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Smad2 Protein
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Smad2 protein, mouse
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Transforming Growth Factor beta
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Vascular Endothelial Growth Factor A
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Wnt Proteins
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Wnt3 Protein
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Wnt3A Protein
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Wnt3a protein, mouse
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beta Catenin
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vascular endothelial growth factor A, mouse
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3
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MAP Kinase Kinase 4
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Lithium Chloride