Author:
Maeda Yuma,Sekiguchi Fumiko,Yamanaka Rumi,Sugimoto Ryo,Yamasoba Daichi,Tomita Shiori,Nishikawa Hiroyuki,Kawabata Atsufumi
Abstract
Abstract
We analyzed signaling mechanisms for prostaglandin E2 (PGE2) production following activation of proteinase-activated receptor-1 (PAR1), a thrombin receptor, in preosteoblastic MC3T3-E1 cells. PAR1 stimulation caused PGE2 release, an effect suppressed by inhibitors of COX-1, COX-2, iPLA2, cPLA2, MAP kinases (MAPKs), Src, EGF receptor (EGFR) tyrosine kinase (EGFR-TK) and matrix metalloproteinase (MMP), but not by an intracellular Ca2+ chelator or inhibitors of PI3 kinase, protein kinase C (PKC) and NF-κB. PAR1 activation induced phosphorylation of MAPKs and upregulation of COX-2. The phosphorylation of p38 MAPK was suppressed by inhibitors of Src and EGFR-TK. The COX-2 upregulation was dependent on ERK, p38, EGFR-TK, Src, and COX-2 itself. PAR1 activation also induced MEK-dependent phosphorylation of cAMP response element binding protein (CREB). All inhibitors of EP1, EP2, EP3 and EP4 receptors suppressed the PAR1-triggered PGE2 release. Exogenously applied PGE2 facilitated PAR1-triggered COX-2 upregulation, but it alone had no effect. Together, the PAR1-mediated PGE2 production in MC3T3-E1 cells appears to involve iPLA2 and cPLA2 for arachidonic acid release, and the MEK/ERK/CREB and Src/MMP/EGFR/p38 pathways for COX-2 upregulation, which is facilitated by endogenous PGE2 formed by COX-2. These signaling mechanisms might underlie the role of the thrombin/PAR1/PGE2 system in the early stage of the bone healing.
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
Reference62 articles.
1. Regulating gene transcription in response to cyclic AMP elevation;Sands;Cell Signal,2008
2. a Mechanisms for prostaglandin formation caused by proteinase - activated receptor activation in rat gastric mucosal epithelial cells;Sekiguchi;Biochem Pharmacol,2007
3. receptor agonists in bone formation and bone healing : in vivoandin vitroevidence Expert;Graham;Invest Drugs,2009
4. - activated receptors in the gastrointestinal system : a functional linkage to prostanoids Inflammopharmacology;Sekiguchi,2007
5. activated receptors contribution to disease;Ossovskaya;physiology Rev,2004
Cited by
10 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献