Abstract: Osteoporosis is the most prevalent of metabolic diseases. Among the treatments for osteoporosis is parathyroid hormone (PTH). PTH has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are unknown. PTH induces primary response genes (PRGs) that will, in turn, activate secondary response genes and ultimately lead to osteoblastic changes. Therefore, studying the first of PTH-induced molecular mediators of osteoblastic differentiation is essential for understanding the PTH anabolic response. Among the PRGs induced by PTH in osteoblasts is the NR4A family of orphan nuclear receptors: Nurr1 and Nur77 and NOR-1. We hypothesize that the PTH induction of NGFI-B participates in the regulation of osteoblastic function based on previous data generated in the laboratory and the ability of Nurr1 and Nur77 to heterodimerize with RXR. In vitro, NOR-1 and Nur77 were PTH-regulated PRGs and were induced mainly through cAMP-PKA pathway. In vivo, PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues. The PTH induction of NR4A pre-mRNA levels suggests that induction of these genes is, at least in part, through activation of mRNA synthesis. Adenovirally-expressed Nurr1 protein bound to the proximal NBRE-like site in chromatin immunoprecipitation (ChIP) assays and induced Ocn mRNA in primary rat osteoblasts. Ocn is a Nurr1 target gene, which positions Nurr1 in the core of transcriptional factors regulating osteoblastic gene expression. The in vitro and in vivo induction of the NR4A family members by PTH and the ability of Nurr1 to bind and transactivate the OCN promoter suggests PTH-induced changes suggests their involvement in bone metabolism. Nuclear receptors are involved in cellular differentiation and several nuclear receptors are important in bone. Thus, we hypothesize that nuclear receptors are important in osteoblastic and differentiation. The NRs pattern of expression is important to help elucidate the mechanism by which nuclear receptors play a role in osteogenic and adipogenic differentiation. We conclude that differential nuclear receptor expression may drive osteoblasts into an adipocyte-like phenotype observed in situations with an apparent decrease in osteoblast differentiation and an increase lipid accumulation.