Interactions between CCAAT enhancer binding protein δ and estrogen receptor α control insulin-like growth factor I (igf1) and estrogen receptor-dependent gene expression in osteoblasts

Although ambient levels of estradiol and synthesis of the osteoblast growth factor IGF-I are inversely related in vivo, estradiol has little or no direct effect on igf1 gene expression in rat osteoblasts in vitro. Rather, estradiol suppresses the effect of hormones that enhance igf1 expression through protein kinase A dependent activation of CCAAT enhancer binding protein (C/EBP) transcription factors. We show here that inhibition of C/EBP activity by estradiol relates to the level of estrogen receptor alpha (ERalpha) expression, and that a complex between hormone-activated ERalpha and C/EBPdelta inhibits transcription by each factor. Protein fragmentation, co-immunoprecipitation, and gene expression studies identified domains for physical and functional interactions between ERalpha and C/EBPdelta. Whereas ERalpha and fragments comprising its various domains associated with C/EBdelta only ERalpha fragment A/B alone replicated the suppressive effect of intact ERalpha on endogenous C/EBPdelta activity. Complementary studies showed that several carboxyl regions of C/EBPdelta cooperatively inhibit ERalpha dependent transcription. Therefore, multiple domains of C/EBPdelta and ERalpha can physically interact to alter gene expression in osteoblasts in selective ways that depend on variations in the local hormone environment. Their combined effects on one important gene target, igf1, may help to determine the balance in the overall rates of bone formation. (C) 2004 Elsevier B.V. All rights reserved.