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J. Biol. Chem., Vol. 278, Issue 21, 18930-18937, May 23, 2003

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Incadronate Amplifies Prostaglandin F₂-induced Vascular Endothelial Growth Factor Synthesis in Osteoblasts

ENHANCEMENT OF MAPK ACTIVITY^*

Haruhiko Tokuda  , Atsushi Harada ¶, Kouseki Hirade , Hiroyuki Matsuno , Hidenori Ito ||, Kanefusa Kato ||, Yutaka Oiso ** and Osamu Kozawa  

From the Department of Internal Medicine, Chubu National Hospital, National Institute for Longevity Sciences, Obu, Aichi 474-8511, Japan, ^¶ Department of Orthopaedics, Chubu National Hospital, National Institute for Longevity Sciences, Obu, Aichi 474-8511, Japan, Department of Pharmacology, Gifu University School of Medicine, Gifu 500-8705, Japan, ^|| Department of Biochemistry, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0391, Japan, ^** First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466-8550, Japan

We have previously reported that prostaglandin F₂ (PGF₂) activates p44/p42 mitogen-activated protein kinase (MAPK) through protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the mechanism of vascular endothelial growth factor (VEGF) synthesis induced by PGF₂ and the effect of incadronate on the VEGF synthesis in these cells. PGF₂ significantly stimulated the VEGF synthesis in a dose-dependent manner between 1 pM and 10 µM. Cycloheximide reduced the PGF₂ effect. PGF₂ increased the levels of mRNA for VEGF. Cloprostenol, a PGF₂-sensitive receptor agonist, potently induced the VEGF synthesis. Indomethacin, an inhibitor of cyclooxygenase, significantly reduced the PGF₂-induced VEGF synthesis. Bisindolylmaleimide, an inhibitor of PKC, reduced the PGF₂-induced VEGF synthesis. The VEGF synthesis induced by PGF₂ was significantly attenuated in the PKC down-regulated cells. PGF₂ elicited the translocation of PKCI from cytosol to membrane fraction. PD98059 or U0126, inhibitors of MEK, suppressed the VEGF synthesis induced by PGF₂. Farnesyltransferase inhibitor failed to affect the PGF₂-induced VEGF synthesis. Incadronate enhanced the synthesis of VEGF induced by PGF₂. NaF-induced VEGF synthesis was also amplified by incadronate. PD98059 suppressed the enhancement by incadronate of PGF₂-induced VEGF synthesis. Incadronate markedly enhanced the phosphorylation of Raf-1, MEK1/2, and p44/p42 MAPK induced by PGF₂ or 12-O-tetradecanoylphorbol-13-acetate, a PKC activator. Incadronate significantly enhanced the cloprostenol-increased level of VEGF concentration in mouse plasma in vivo. These results strongly suggest that PGF₂ stimulates VEGF synthesis through the PKC-dependent activation of p44/p42 MAPK in osteoblasts and that the incadronate enhances the VEGF synthesis at the point between PKC and Raf-1.

Received for publication, September 6, 2002 , and in revised form, March 17, 2003.

To whom correspondence should be addressed. Tel.: 81-58-2672231; Fax: 81-58-267-2959; E-mail: okozawa{at}cc.gifu-u.ac.jp.

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