Parathyroid hormone (PTH) binds to its receptor on osteoblasts to regulate gene transcription primarily through the elevation of the second messenger cAMP. A number of genes regulated by PTH in osteoblasts contain GC-rich and Sp-binding sites. Osterix (Osx, Sp7) is a transcription factor required for the differentiation of osteoblasts that can bind to Sp-binding sites on gene promoters and regulate their expression. Here, we report the effect of PTH (1-34) on Osx expression in osteoblastic UMR-106-01 cells and murine calvaria. PTH (1-34) and PTH (1-31) inhibited Osx mRNA and protein expression, and this effect could be mimicked by forskolin, 8-bromo-cAMP, or expression of constitutively active Gsa (caGsa). Treatment of the cells with PTH (3-34) or the EPAC-selective agonist 8CPT-2Me-cAMP had no effect on Osx mRNA, whereas PTH (7-34) or expression of caGqa-stimulated Osx mRNA levels. PTH (1-34) treatment did not require new protein synthesis and did not involve changes in Osx mRNA stability. Osx promoter fragments coupled to a luciferase reporter were inhibited by PTH (1-34) treatment in a similar manner to the inhibition of Osx mRNA and protein.Deletion analysis localized PTH inhibition to two regions flanking the Osx1 start site; K304/K119 and K71/C91. These results demonstrate that prolonged exposure to PTH inhibits Osx expression in osteoblasts through sites on its proximal promoter and this suppression occurs through PTH stimulation of cellular cAMP.
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