title: Wnt3a upregulates transforming growth factor-β-stimulated VEGF synthesis in osteoblasts.
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.
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Natsume
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Kato
authors.forename: Kengo
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000187:drug effects / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger; D015398:Signal Transduction; D051899:Smad2 Protein / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism* / Q000494:pharmacology; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D012333:RNA, Messenger; C417521:SB 216763; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; C467480:vascular endothelial growth factor A, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D048670:MAP Kinase Kinase 4; D018021:Lithium Chloride