Prostaglandins (PGs) play an important role in bone remodeling because eicosanoids are local mediators of bone metabolism, which can induce physiological and pathological responses of bone tissue. Biosynthesis of PGs is catalyzed by constitutively expressed PG endoperoxide G/H synthase (PGHS) 1 and by the inducible isoform PGHS-2. In MC3T3-E1 osteoblast-like cells, expression of PGHS-2 was shown by mechanical forces, cytokines, growth factors, and hormones. Recently, endothelin (ET) 1-stimulated PGHS-2 mRNA expression was described, leading to a burst in prostaglandin E2 (PGE2) production. In this study, we investigated ET-1-induced signal transduction pathway(s) involved in the PGHS-2 mRNA production. Time course of PGHS-2 mRNA expression reaching the maximum within 45 minutes is in good agreement with the concept of an immediate early gene product. Inhibition of phospholipase C (PLC), phospholipase D (PLD), phosphatidylinositol-3 kinase (PI-3-kinase), and protein kinase C (PKC) had no influence on PGHS-2 synthesis. Using specific blockers of tyrosine kinases indicated involvement of p38 MAPK but not p42/44 MAPK. By preloading cells with exoenzyme C3, we were able to show requirement of the Rho family of G proteins for p38 MAPK phosphorylation and PGHS-2 mRNA synthesis, whereas pertussis toxin (PTX) and cholera toxin (CTX) had no remarkable effect.