Stress-activated protein kinase/c-Jun N-terminal kinase (JNK) plays a part in endothelin-1-induced vascular endothelial growth factor synthesis in osteoblasts.

Abstract

We previously reported that endothelin-1 (ET-1) activates both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that not p44/p42 MAP kinase but p38 MAP kinase participates in the ET-1-induced vascular endothelial growth factor (VEGF) synthesis. In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (JNK) in ET-1-induced VEGF synthesis in these cells. ET-1 significantly induced the phosphorylation of JNK in a dose-dependent manner in the range between 0.1 and 100 nM. SP600125, an inhibitor of JNK, markedly reduced the ET-1-induced VEGF synthesis. A combination of SP600125 and SB203580 additively reduced the ET-1-stimulated VEGF synthesis. SP600125 suppressed the ET-1-induced phosphorylation of JNK, while having no effect on the phosphorylation of p38 MAP kinase elicited by ET-1. SB203580, an inhibitor of p38 MAP kinase, hardly affected the ET-1-induced phosphorylation of JNK. These results strongly suggest that JNK plays a role in ET-1-induced VEGF synthesis in addition to p38 MAP kinase in osteoblasts.