Fiche publication
Date publication
avril 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Borjesson AE, Windahl SH, Lagerquist MK, Engdahl C, Frenkel B, Moverare-Skrtic S, Sjogren K, Kindblom JM, Stubelius A, Islander U, Antal MC, Krust A, Chambon P, Ohlsson C
Lien Pubmed
Résumé
The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-alpha (ERalpha), 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 ERalpha AF-1 and ERalpha AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERalpha protein (ERalpha(-/-)), ERalpha AF-1 (ERalphaAF-1(0)), or ERalpha AF-2 (ERalphaAF-2(0)). 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 ERalpha(-/-) or OVX ERalphaAF-2(0) mice. OVX ERalphaAF-1(0) 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 ERalpha(-/-) or OVX ERalphaAF-2(0) mice. The effect of E2 in OVX ERalphaAF-1(0) mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ERalpha AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERalpha AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERalpha with minimal activation of ERalpha AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.
Référence
Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6288-93
