Parathyroid hormone induces expression of the nuclear orphan receptor Nurr1 in bone cells

Following PTH treatment, immediate changes in osteoblast gene expression involve induction of primary response genes. Primary gene products subsequently mediate the osteoblast response to PTH. Using representational difference analysis (RDA) to isolate primary genes induced by PTH in osteoblasts, we identified Nurr1, a member of the NGFI-B nuclear orphan receptor subfamily. Nurr1 binds DNA as a monomer but also heterodimerizes with the 9-cis retinoic acid receptor (RXR). Nurr1's importance in retinoic acid, vitamin D, and thyroid hormone signaling has been hypothesized. Nurr1 messenger RNA (mRNA) levels were maximal at 1 h and at 10 nM of PTH in primary mouse osteoblasts (MOB). Activation of the PKA and PKC pathways by 10 microM forskolin and 1 microM PMA, respectively, induced Nurr1 mRNA levels. However, inhibition of the PKA but not the PKC pathway significantly inhibited the PTH induction of Nurr1. Moreover, PTH(3-34) at 1-100 nM did not induce Nurr1 mRNA levels. Thus, PTH induction of Nurr1 in primary mouse osteoblasts is mediated primarily through the cAMP/PKA pathway. PTH also stimulated Nurr1 protein in MOB cells and Nurr1 mRNA in calvarial organ cultures. Nurr1 induction represents a potential cross-talk mechanism between PTH and steroid hormone signaling at the transcription factor level.