PTH-Induced NGFI-B Proteins Regulate Osteoblast Function

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DESCRIPTION (provided by applicant): Anabolic treatments that restore bone health improve clinical outcomes in dentistry and medicine. Parathyroid hormone (PTH) has significant anabolic effects on bone metabolism. However, the molecular mediators of PTH's anabolic effects remain unclear. Our research focuses on PTH-induced primary genes that act as transcription factors to target late gene expression and propagate changes in osteoblastic function. We have identified NGFI-B nuclear orphan receptors (Nurr1, Nur77, NOR-1) as PTH-induced primary genes in osteoblasts. NGFI-B proteins regulate transcription and cellular differentiation through NGFI-B response elements (NBREs) in target gene promoters. Nurr1 protein transactivated the rat osteocalcin promoter through a wild type (WT), but not mutant (mut), NBRE. PTH induced the PPARgamma coactivator PGC-1alpha. PGC-1alpha, in turn, strongly enhanced Nurr1-induced transactivation of the WT, but no mut, OCN promoter, suggesting that Nurr1 binding to the NBRE is critical in transcriptosome assembly on NGFI-B target promoters. We observed that the consensus PPARgamma response element (PPRE) contains an NBRE. Indeed, recombinant and PTH-induced Nurr1 protein bound to a consensus PPRE. Intriguingly, in addition to synergizing with PGC1alpha, Nurr1 and Nur77 also heterodimerize with PPARgamma's obligatory partner, RXR. These data suggest that NGFI-B and PPARgamma, signaling may converge on PPRE-containing promoters. We propose that NGFI-B proteins downregulate PPARgamma-responsive genes thereby promoting osteogenesis over adipogenesis. To that effect, PTH inhibited the PPARg, target gene CD36 in primary osteoblasts. We hypothesize that NGFI-B genes are critical mediators of osteoblast differentiation and function through target promoter regulation and selective cofactor recruitment. Our Specific Aims are to: 1) study transcription regulation by NGFI-B nuclear orphan receptors in osteoblasts, 2) examine PTH-induction of and NGFI-B interactions with PGC-1alpha, 3) investigate the effect of targeted NGFI-B overexpression on bone in vivo.