Isoflavones suppress cyclic adenosine 3',5'-monophosphate regulatory element-mediated transcription in osteoblastic...

Soy isoflavones have been implicated to exert benefit on bone loss in postmenopausal women. Isoflavones can induce estrogen response element-mediated transcription in osteoblastic cells. In the present study, we investigate whether isoflavones genistein and daidzein regulate target gene transcription through cAMP regulatory element (CRE) in osteoblastic cells. It was found that 17β-estradiol (E(2)), genistein and daidzein suppressed the transcriptional activity of CRE-luciferase reporter gene in human osteoblastic cell line MG-63 cells. E(2) and genistein but not daidzein inhibited the cAMP analogue 8-Br cAMP-induced transcription of CRE reporter gene. Both genistein and E(2) inhibited basal and cAMP-induced mRNA levels of endogenous estrogen responsive genes containing CRE/CRE-like elements in their promoter regions, including interleukin (IL) 8 and serum- and glucocorticoid-inducible kinase 1 (SGK1). Daidzein inhibited basal and cAMP-induced IL-8, but not SGK1 mRNA expression. The inhibitory effects of E(2), genistein and daidzein on CRE-mediated transcription activity were enhanced by estrogen receptor (ER) α overexpression in MG-63 cells, which could be blocked by nonselective ER antagonists ICI182780, 4-OH tamoxifen and specific ERα antagonist MPP. Genistein and daidzein, but not E(2) treatment, caused a significant decrease in CRE-mediated transcription activity in ERβ-transfected MG-63 cells, which could be blocked by ICI182780, 4-OH tamoxifen and the selective ERβ antagonist (R,R)-5,11-diethyl-5.6,11,12-tetradro-2,8-chrysenediol. Our results indicate that isoflavones genistein and daidzein might modulate bone remodeling through ERs by regulating target gene expression through the CRE motifs.