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We analyzed signaling mechanisms for prostaglandin E 2  (PGE 2 ) production following activation of proteinase-activated receptor-1 (PAR1), a thrombin receptor, in preosteoblastic MC3T3-E1 cells. PAR1 stimulation caused PGE 2  release, an effect suppressed by inhibitors of COX-1, COX-2, iPLA 2 , cPLA 2 , MAP kinases (MAPKs), Src, EGF receptor (EGFR) tyrosine kinase (EGFR-TK) and matrix metalloproteinase (MMP), but not by an intracellular Ca 2+  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 PGE 2  release. Exogenously applied PGE 2  facilitated PAR1-triggered COX-2 upregulation, but it alone had no effect. Together, the PAR1-mediated PGE 2  production in MC3T3-E1 cells appears to involve iPLA 2  and cPLA 2  for arachidonic acid release, and the MEK/ERK/CREB and Src/MMP/EGFR/p38 pathways for COX-2 upregulation, which is facilitated by endogenous PGE 2  formed by COX-2. These signaling mechanisms might underlie the role of the thrombin/PAR1/PGE 2  system in the early stage of the bone healing.

Mechanisms for proteinase-activated receptor 1-triggered prostaglandin E 2 generation in mouse osteoblastic MC3T3-E1 cells