FGF-8 stimulates the expression of NR4A orphan nuclear receptors in osteoblasts

Nurr1, NGFI-B, and Nor1 form the NR4A subfamily of orphan nuclear receptors. The NR4A receptors are immediate early genes that can be rapidly induced in response to a variety of stimuli in many cell types, for example, in osteoblasts. Nurr1 regulates the differentiation of osteoblasts and the expression of several osteoblastic genes. Fibroblast growth factor 8b (FGF-8b) regulates osteoblastic differentiation. We show here that treatment of preosteoblastic MC3T3-E1 cells or mouse bone marrow mesenchymal cells with FGF-8b induces the expression of NR4A receptors rapidly and in a dose-dependent manner. This induction involves mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI-3K), and protein kinase C (PKC) pathways. FGF-8b stimulates the proliferation of MC3T3-E1 cells. This effect is enhanced by overexpression of Nurr1 and NGFI-B whereas it is abolished by a dominant negative Nurr1 variant. In conclusion, FGF-8b induces the expression of NR4A orphan nuclear receptors that are involved in mediating the growth promoting effect of FGF-8b in osteoblasts.