title: Resveratrol suppresses TGF-β-induced VEGF synthesis in osteoblasts: Inhibition of the p44/p42 MAPKs and SAPK/JNK pathways.
abstract: Resveratrol, which is found in grape and berry skins and red wine, is generally known to be beneficial for human health due to its anti-inflammation and antioxidant effects. We have recently reported that transforming growth factor-β (TGF-β) stimulates vascular endothelial growth factor (VEGF) synthesis through Smad-independent pathways, such as the p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways, in osteoblast-like MC3T3-E1 cells. The aim of the present study was to investigate the effect of resveratrol on the TGF-β-induced VEGF synthesis and the mechanism in osteoblast-like MC3T3-E1 cells. Resveratrol significantly suppressed the TGF-β-stimulated release of VEGF and the VEGF mRNA expression levels. SRT1720, a synthetic sirtuin 1 (SIRT1) activator, also reduced the VEGF release and the mRNA levels. With regard to the intracellular signaling in the TGF-β-stimulated VEGF synthesis, resveratrol and SRT1720 significantly attenuated the phosphorylation of p44/p42 MAP kinase and SAPK/JNK stimulated by TGF-β; however, the TGF-β-induced phosphorylation of Smad2 and p38 MAP kinase was hardly affected by resveratrol or SRT1720. These results strongly suggest that the TGF-β-stimulated VEGF synthesis is suppressed by resveratrol through the inhibition of p44/p42 MAP kinase and SAPK/JNK in osteoblasts, and that the suppressive effect is mediated, at least in part, via SIRT1 activation.
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Chubu 467-8601, Japan ; Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Kuroyanagi
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Chubu 467-8601, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Chubu 467-8601, Japan ; Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan ; Department of Clinical Laboratory, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
keywords: osteoblast; resveratrol; transforming growth factor-β; vascular endothelial growth factor