title: Mechanisms for proteinase-activated receptor 1-triggered prostaglandin E2 generation in mouse osteoblastic MC3T3-E1 cells.
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.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Maeda
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Rumi
authors.initials: R
authors.lastname: Yamanaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Sugimoto
authors.forename: Daichi
authors.initials: D
authors.lastname: Yamasoba
authors.forename: Shiori
authors.initials: S
authors.lastname: Tomita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015232:Dinoprostone / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts; D010766:Phosphorylation; D044463:Receptor, PAR-1 / Q000378:metabolism*
chemical_list: D044463:Receptor, PAR-1; D015232:Dinoprostone