A DNA binding mutation in estrogen receptor-α leads to suppression of Wnt signaling via β-catenin destabilization in osteoblasts.
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
References
Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways.
Citations
Related Concepts
Related Feeds
CREs: Gene & Cell Therapy
Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.