Cross-talk between NR4A orphan nuclear receptors and β-catenin signaling pathway in osteoblasts

The canonical Wnt signaling pathway and its key mediator beta-catenin are important regulators of osteoblast function. NR4A orphan nuclear receptors (Nurr1, NGFI-B, and Nor 1) are expressed in osteoblasts and have been shown to regulate the expression of osteoblastic genes and osteoblastic differentiation. Recently, interplay between Nurrl and the canonical Wnt signaling pathway was reported in 293F cells. We have studied the potential interplay between NR4A receptors and beta-catenin in osteoblasts. NR4A receptors repressed beta-catenin-mediated transactivation when cotransfected in U2-OS cells. In addition, Nurrl inhibited beta-catenin-mediated expression of Axin2 in MC3T3-E1 cells. The repression involved the DNA-binding domain of NR4A receptors. The repression of beta-catenin did not result from reduced beta-catenin expression or direct protein-protein interaction between beta-catenin and NR4A receptors. beta-Catenin was capable of inhibiting the transcriptional activity of NR4A receptors in U2-OS cells by a mechanism that involved the ligand-binding domain of NR4A receptors. As the canonical Wnt signaling pathway and beta-catenin are crucial for the development and function of osteoblasts, the repressive effect of NR4A receptors on beta-catenin is of potential biological and pathophysiological importance. (C) 2011 Elsevier Inc. All rights reserved.