Roles of transactivating functions 1 and 2 of estrogen receptor-α in bone

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-alpha (ER alpha), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ER alpha AF-1 and ER alpha AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ER alpha protein (ER alpha(-/-)), ER alpha AF-1 (ER alpha AF-1 degrees), or ER alpha AF-2 (ER alpha AF-2 degrees). Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WT mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ER alpha(-/-) or OVX ER alpha AF-2 degrees mice. OVX ER alpha AF-1 degrees mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ER alpha(-/-) or OVX ER alpha AF-2 degrees mice. The effect of E2 in OVX ER alpha AF-1 degrees mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ER alpha AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ER alpha AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ER alpha with minimal activation of ER alpha AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.