title: Regulation by resveratrol of prostaglandin E2-stimulated osteoprotegerin synthesis in osteoblasts.
abstract: Resveratrol is a natural polyphenol found in red grape skins, berries and red wine. Accumulating evidence suggests that resveratrol has various beneficial effects on the human body. In the present study, we investigated the effects of prostaglandin E(2) (PGE(2)) on osteoprotegerin (OPG) synthesis and the effects of resveratrol on OPG synthesis in osteoblast-like MC3T3-E1 cells. PGE(2) significantly stimulated both the release of OPG and the mRNA expression levels of OPG, as shown by OPG assay and real-time RT-PCR, respectively. Resveratrol markedly suppressed the release and the mRNA levels of OPG induced by PGE(2). On the contrary, SRT1720, an activator of sirtuin 1 (SIRT1), hardly affected the PGE(2)-induced release of OPG. PD98059 [a specific inhibitor of the upstream kinase that activates p44/p42 mitogen-activated protein (MAP) kinase], SB203580 (a specific inhibitor of p38 MAP kinase) and SP600125 [a specific inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)], reduced the PGE(2)-induced release of OPG. Resveratrol attenuated the PGE(2)-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK. However, SRT1720 failed to affect the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK induced by PGE(2). These results strongly suggest that resveratrol reduces PGE(2)-stimulated OPG synthesis through the inhibition of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK in osteoblasts, and that these suppressive effects are independent of the activation of SIRT1.
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, 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: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, 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 467-8601, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mizutani
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 Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kondo
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 Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000096:biosynthesis*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000873:Anthracenes; D007093:Imidazoles; D053244:Osteoprotegerin; D011725:Pyridines; D013267:Stilbenes; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D015232:Dinoprostone; C093642:SB 203580; D000077185:Resveratrol