title: Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts.
abstract: We have previously reported that prostaglandin F2alpha (PGF2alpha) activates p44/p42 mitogen-activated protein (MAP) kinase through protein kinase C (PKC), resulting in the synthesis of vascular endothelial growth factor (VEGF) in osteoblast-like MC3T3-E1 cells, and that incadronate, a bisphosphonate, amplifies the VEGF synthesis. In the present study, we investigated the effects of tiludronate and etidronate, other bisphosphonates, on the PGF2alpha-stimulated VEGF synthesis in these cells. Tiludronate reduced the synthesis of VEGF induced by PGF2alpha. The PGF(2alpha)-stimulated phosphorylation of p44/p42 MAP kinase was suppressed by tiludronate. On the other hand, etidronate affected neither the VEGF synthesis nor the phosphorylation of p44/p42 MAP kinase elicited by PGF2alpha. Tiludronate attenuated the phosphorylation of both Raf-1 and MEK1/2 induced by PGF2alpha. The VEGF synthesis stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator of PKC, was suppressed by tiludronate. The TPA-induced phosphorylations of Raf-1, MEK1/2 and p44/p42 MAP kinase were inhibited by tiludronate. These results strongly suggest that tiludronate but not etidronate suppresses the PGF2alpha-stimulated VEGF synthesis in osteoblasts, and that the effect of tiludronate is exerted at the point between PKC and Raf-1.
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kanno
authors.forename: Atsushi
authors.initials: A
authors.lastname: Harada
authors.forename: Katsuji
authors.initials: K
authors.lastname: Shimuzu
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015237:Dinoprost / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D012968:Etidronic Acid / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D004164:Diphosphonates; D042461:Vascular Endothelial Growth Factor A; C058651:tiludronic acid; D015237:Dinoprost; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012968:Etidronic Acid