The estrogen receptors (ER) and are important ligand mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for over a decade, little data exists concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGF Inducible Early Gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ER, but not ER. We have identified the regulatory elements utilized by ER and have demonstrated that ER recruits SRC1 and SRC2 to this regulatory region. Additionally, deletion of the ER-AF1 domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ER is responsible for recruiting SRC1 and SRC2, and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ER. Overall, these data demonstrate that the estrogen induction of TIEG is ER specific and that the AF1 domain of ER confers this specificity. Finally, a novel and important role for ER's AF1 is implicated in the recruitment of specific co-activators suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.