Aromatase expression in a human osteoblastic cell line increases in response to prostaglandin E 2 in a dexamethasone-dependent fashion

Abstract

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) E 2 induces estrogen production, in other words, if PGE 2 exerts the same effect as FSK because PGE 2 is the major prostanoid in the bone and is one of the key molecules in the osteoblast. We found PGE 2 up-regulates aromatase activity synergistically, but this up-regulation depends on Dex. CYP19 gene expression was also increased synergistically by Dex and PGE 2. Promoter I.4 was activated synergistically by PGE 2 and Dex. PGE 2 receptor, EP 1, EP 2 and EP 4 were involved in the up-regulation of aromatase activity in response to PGE 2 in a Dex-dependent manner. The cAMP-PKA pathway and Ca 2+ signaling pathway were involved in the up-regulation of aromatase activity in response to PGE 2. Furthermore, glucocorticoid response element on promoter I.4 sequence was an essential minimum requirement for its activity and synergism of PGE 2 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 PGE 2 produced in bone mainly may synergistically support local estrogen production in osteoblastic cells in the presence of glucocorticoid.