Estrogen receptor‐α is required for the osteogenic response to mechanical loading in a ligand‐independent manner involving its activation function 1 but not 2

• Published in: Journal of bone and mineral research 2013-02, Vol.28 (2), p.291-301
• Main Authors: Windahl, Sara H, Saxon, Leanne, Börjesson, Anna E, Lagerquist, Marie K, Frenkel, Baruch, Henning, Petra, Lerner, Ulf H, Galea, Gabriel L, Meakin, Lee B, Engdahl, Cecilia, Sjögren, Klara, Antal, Maria C, Krust, Andrée, Chambon, Pierre, Lanyon, Lance E, Price, Joanna S, Ohlsson, Claes
• Format: Article
• Language: English
• Subjects: Animals; BONE; Clinical Medicine; Cyclooxygenase 2 - metabolism; Early Growth Response Protein 2 - genetics; Early Growth Response Protein 2 - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Estradiol - metabolism; ESTROGEN; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - metabolism; Female; Gene Expression Regulation; Interleukin-11 - genetics; Interleukin-11 - metabolism; Klinisk medicin; Ligands; LOADING; Luciferases - metabolism; MECHANICAL; Mice; Mice, Inbred C57BL; Mice, Transgenic; MOUSE; Original; Osteogenesis - genetics; RECEPTOR; Response Elements - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stress, Mechanical; Tibia - physiology; Weight-Bearing
• ISSN: 0884-0431; 1523-4681; 1523-4681
• DOI: 10.1002/jbmr.1754

Estrogen receptor‐α (ERα) 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 ERα domains for the osteogenic response to mechanical loading, gene‐targeted mouse models with (1) a complete ERα inactivation (ERα−/−), (2) specific inactivation of activation function 1 (AF‐1) in ERα (ERαAF‐10), or (3) specific inactivation of ERαAF‐2 (ERαAF‐20) 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 ERα−/− mice displayed a severely reduced osteogenic response to loading with changes in cortical area (−78% ± 15%, p