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

The canonical Wnt signaling pathway and its key mediator β-catenin are important regulators of osteoblast function. NR4A orphan nuclear receptors (Nurr1, NGFI-B, and Nor1) are expressed in osteoblasts and have been shown to regulate the expression of osteoblastic genes and osteoblastic differentiation. Recently, interplay between Nurr1 and the canonical Wnt signaling pathway was reported in 293F cells. We have studied the potential interplay between NR4A receptors and β-catenin in osteoblasts. NR4A receptors repressed β-catenin-mediated transactivation when cotransfected in U2-OS cells. In addition, Nurr1 inhibited β-catenin-mediated expression of Axin2 in MC3T3-E1 cells. The repression involved the DNA-binding domain of NR4A receptors. The repression of β-catenin did not result from reduced β-catenin expression or direct protein-protein interaction between β-catenin and NR4A receptors. β-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 β-catenin are crucial for the development and function of osteoblasts, the repressive effect of NR4A receptors on β-catenin is of potential biological and pathophysiological importance.