Rho-kinase limits FGF-2-stimulated VEGF release in osteoblasts

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• 作者：Hideo Natsume ; Haruhiko Tokuda ; Seiji Adachi ; Shinji Takai ; Rie Matsushima-Nishiwaki ; Kenji Kato ; Chiho Minamitani ; Shunpei Niida ; Jun Mizutani ; Osamu Kozawa ; Takanobu Otsuka
• 关键词：Rho-kinase ; MAP kinase ; FGF-2 ; VEGF ; Osteoblast
• 刊名：Bone
• 出版年：2010
• 出版时间：April 2010
• 年：2010
• 卷：46
• 期：4
• 页码：1068-1074
• 全文大小：436 K

文摘

We previously reported that basic fibroblast growth factor (FGF-2) stimulates the release of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates the VEGF release in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether Rho-kinase is involved in FGF-2-stimulated VEGF release in MC3T3-E1 cells. FGF-2 induced the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase. Y27632, a specific inhibitor of Rho-kinase, which attenuated the MYPT-1 phosphorylation, significantly enhanced the FGF-2-stimulated VEGF release. Fasudil, another Rho-kinase inhibitor, also amplified the VEGF release. FGF-2 significantly stimulated VEGF accumulation and fasudil enhanced FGF-2-stimulated VEGF accumulation also in whole cell lysates. Neither Y27632 nor fasudil affected the phosphorylation levels of p44/p42 MAP kinase or p38 MAP kinase. Y27632 and fasudil markedly strengthened the FGF-2-induced phosphorylation of SAPK/JNK. Y27632 as well as fasudil enhanced FGF-2-stimulated VEGF release and Y27632 enhanced the FGF-2-induced phosphorylation levels of SAPK/JNK also in human osteoblasts. These results strongly suggest that Rho-kinase negatively regulates FGF-2-stimulated VEGF release in osteoblasts.