A DNA binding mutation in estrogen receptor-α leads to suppression of Wnt signaling via β-catenin destabilization in osteoblasts.

Journal of Cellular Biochemistry
Ulrike I MödderDavid G Monroe

Abstract

Estrogen receptors (ERs) play vital roles in the function and remodeling of bone. Their cellular mechanisms can broadly be categorized into those involving direct DNA binding (classical) or indirect DNA binding (non-classical). The generation of non-classical ER knock-in (ERα(-/NERKI) ) mice provides a unique opportunity to define these pathways in bone. We previously demonstrated that ERα(-/NERKI) mice exhibit an osteoporotic phenotype; however, the mechanism(s) for this remain unresolved. Gene expression analyses of cortical bone from ERα(-/NERKI) mice revealed suppression of lymphoid enhancer factor-1 (Lef1), a classic Wnt-responsive transcription factor that associates with β-catenin. Since Wnt signaling is generally considered bone anabolic, this observation leads to the hypothesis that NERKI-induced suppression of Wnt signaling may contribute to the low bone mass phenotype. We generated ERα(-/NERKI) mice crossed with the Wnt-responsive TOPGAL transgenic mouse model and observed significantly less β-galactosidase activity in ERα(-/NERKI) mice, confirming suppression of Wnt activity in vivo. Adenoviral expression of the NERKI receptor using an in vitro cell system resulted in the induction of several secreted antagonists of...Continue Reading

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Citations

Oct 16, 2018·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Ruben Aquino-MartinezDavid G Monroe
Sep 10, 2014·Endocrine Reviews·Dirk VanderschuerenClaes Ohlsson
Oct 18, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jorma A MäättäKalervo Väänänen
Apr 10, 2014·Molecular Endocrinology·Sylvia C HewittKenneth S Korach

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