Aromatase expression in a human osteoblastic cell line increases in response to prostaglandin E2 in a dexamethasone-dependent fashion

Recent progress supports the importance of local estrogen secretion in human bone tissue to increase and maintain bone-mineral density. In a previous report, we found that forskolin (FSK) synergistically induces aromatase (CYP19: a rate-limiting enzyme for estrogen synthesis) expression in dexamethasone (Dex) dependent manner in a human osteoblastic cell line, SV-HFO [Watanabe M, Ohno S, Nakajin S. Forskolin and dexamethasone synergistically induce aromatase (CYP19) expression in the human osteoblastic cell line SV-HFO. Eur J Endocrinol 2005;152:619–24]. In this report, we investigated whether prostaglandin (PG) E2 induces estrogen production, in other words, if PGE2 exerts the same effect as FSK because PGE2 is the major prostanoid in the bone and is one of the key molecules in the osteoblast. We found PGE2 up-regulates aromatase activity synergistically, but this up-regulation depends on Dex. CYP19 gene expression was also increased synergistically by Dex and PGE2. Promoter I.4 was activated synergistically by PGE2 and Dex. PGE2 receptor, EP1, EP2 and EP4 were involved in the up-regulation of aromatase activity in response to PGE2 in a Dex-dependent manner. The cAMP-PKA pathway and Ca2+ signaling pathway were involved in the up-regulation of aromatase activity in response to PGE2. Furthermore, glucocorticoid response element on promoter I.4 sequence was an essential minimum requirement for its activity and synergism of PGE2 and Dex. These findings are the first report on osteoblastic cell line which uses predominantly promoter I.4 to drive aromatase expression. These findings also suggest that endogenous PGE2 produced in bone mainly may synergistically support local estrogen production in osteoblastic cells in the presence of glucocorticoid.