Estrogen Receptor (ER)- Reduces ER -Regulated Gene Transcription, Supporting a “Ying Yang” Relationship between ER and ER in Mice

Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor(ER ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ER inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ER -inactivated than in WT mice, demonstrating that ER reduces estrogen receptor(ER )-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ER -inactivated mice was intermediate between that seen in WT and ER double-inactivated mice. Thus, ER inhibits ER -mediated gene transcription in the presence of ER , whereas, in the absence of ER , it can partially replace ER . In conclusion, our in vivo data indicate that an important physiological role of ER is to modulate ER mediated gene transcription supporting a “Ying Yang” relationship between ER and ER in mice. (Molecular Endocrinology 17: 203–208, 2003)