Estrogen receptor-alpha is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2.
Fiche publication
Date publication
février 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Windahl SH, Saxon L, Borjesson AE, Lagerquist MK, Frenkel B, Henning P, Lerner UH, Galea GL, Meakin LB, Engdahl C, Sjogren K, Antal MC, Krust A, Chambon P, Lanyon LE, Price JS, Ohlsson C
Lien Pubmed
Résumé
Estrogen receptor-alpha (ERalpha) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERalpha domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERalpha inactivation (ERalpha(-/-) ), (2) specific inactivation of activation function 1 (AF-1) in ERalpha (ERalphaAF-1(0) ), or (3) specific inactivation of ERalphaAF-2 (ERalphaAF-2(0) ) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ERalpha(-/-) mice displayed a severely reduced osteogenic response to loading with changes in cortical area (-78% +/- 15%, p < 0.01) and periosteal BFR (-81% +/- 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ERalphaAF-1(0) mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area -40% +/- 11%, p < 0.05 and periosteal BFR -41% +/- 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ERalphaAF-2(0) mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERalpha is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2.
Référence
J Bone Miner Res. 2013 Feb;28(2):291-301