Tokuda H, Hirade K, Wang X, Oiso Y, Kozawa O
Department of Internal Medicine, Chubu National Hospital - National Institute for Longevity Sciences, Obu, Aichi 474-8511, Japan.
J Endocrinol. 2003 Apr;177(1):101-7. doi: 10.1677/joe.0.1770101.
We previously reported that basic fibroblast growth factor (FGF-2) activates 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 VEGF release. In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in FGF-2-induced VEGF release in these cells. FGF-2 markedly induced the phosphorylation of SAPK/JNK. SP600125, an inhibitor of SAPK/JNK, markedly reduced the FGF-2-induced VEGF release. SP600125 suppressed the FGF-2-induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p44/p42 MAP kinase or p38 MAP kinase induced by FGF-2. PD98059, an inhibitor of upstream kinase of p44/p42 MAP kinase, or SB203580, an inhibitor of p38 MAP kinase, failed to affect the FGF-2-induced phosphorylation of SAPK/JNK. A combination of SP600125 and SB203580 suppressed the FGF-2-stimulated VEGF release in an additive manner. These results strongly suggest that FGF-2 activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a part in FGF-2-induced VEGF release.
我们先前报道，碱性成纤维细胞生长因子（FGF-2）激活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释放起负调控作用。在本研究中，我们调查了应激激活蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）在FGF-2诱导这些细胞释放VEGF过程中的作用。FGF-2显著诱导SAPK/JNK的磷酸化。SAPK/JNK抑制剂SP600125显著降低FGF-2诱导的VEGF释放。SP600125抑制FGF-2诱导的SAPK/JNK磷酸化，而不影响FGF-2诱导的p44/p42 MAP激酶或p38 MAP激酶的磷酸化。p44/p42 MAP激酶上游激酶抑制剂PD98059或p38 MAP激酶抑制剂SB203580未能影响FGF-2诱导的SAPK/JNK磷酸化。SP600125和SB203580联合使用以相加的方式抑制FGF-2刺激的VEGF释放。这些结果有力地表明，FGF-2在成骨细胞中激活SAPK/JNK，且SAPK/JNK在FGF-2诱导的VEGF释放中起作用。
