Yasuda Eisuke, Tokuda Haruhiko, Ishisaki Akira, Hirade Kouseki, Kanno Yosuke, Hanai Yoshiteru, Nakamura Norimi, Noda Takahiro, Katagiri Yoshihiro, Kozawa Osamu
Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Biochem Biophys Res Commun. 2005 Mar 4;328(1):137-43. doi: 10.1016/j.bbrc.2004.12.163.
We previously reported that basic fibroblast growth factor (FGF-2) activates stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p44/p42 mitogen-activated protein (MAP) kinase resulting in the stimulation of vascular endothelial growth factor (VEGF) release in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates the VEGF release. In the present study, we investigated the effects of ciglitazone and pioglitazone, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands, on the VEGF release by FGF-2 in MC3T3-E1 cells. The FGF-2-induced VEGF release was significantly enhanced by ciglitazone. The amplifying effect of ciglitazone was dose-dependent between 0.1 and 10 microM. Pioglitazone had a similar effect on the VEGF release. GW9662, an antagonist of PPAR-gamma, reduced the effects of ciglitazone and pioglitazone. Ciglitazone or pioglitazone markedly enhanced the phosphorylation of SAPK/JNK induced by FGF-2 without affecting both the FGF-2-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. GW9662 markedly reduced the amplification by ciglitazone of the SAPK/JNK phosphorylation. Taken together, these results strongly suggest that PPAR-gamma ligands up-regulate FGF-2-stimulated VEGF release resulting from amplifying activation of SAPK/JNK in osteoblasts.
我们先前报道，碱性成纤维细胞生长因子（FGF-2）可激活应激激活蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）和p44/p42丝裂原活化蛋白（MAP）激酶，从而刺激成骨样MC3T3-E1细胞释放血管内皮生长因子（VEGF），且FGF-2激活的p38 MAP激酶对VEGF释放起负性调节作用。在本研究中，我们调查了过氧化物酶体增殖物激活受体γ（PPAR-γ）配体环格列酮和吡格列酮对MC3T3-E1细胞中FGF-2诱导的VEGF释放的影响。环格列酮可显著增强FGF-2诱导的VEGF释放。在0.1至10微摩尔之间，环格列酮的放大作用呈剂量依赖性。吡格列酮对VEGF释放有类似作用。PPAR-γ拮抗剂GW9662可降低环格列酮和吡格列酮的作用。环格列酮或吡格列酮可显著增强FGF-2诱导的SAPK/JNK磷酸化，而不影响FGF-2诱导的p44/p42 MAP激酶和p38 MAP激酶的磷酸化。GW9662可显著降低环格列酮对SAPK/JNK磷酸化的放大作用。综上所述，这些结果强烈表明，PPAR-γ配体通过增强成骨细胞中SAPK/JNK的激活来上调FGF-2刺激的VEGF释放。
