Proto-Oncogene c-fos Is Transcriptionally Regulated by Parathyroid Hormone (PTH) and PTH-Related Protein in a Cyclic Adenosine Monophosphate-Dependent Manner in Osteoblastic Cells

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Abstract
PTH and PTH-related protein (PTHrP) bind to the PTH-1 (PTH/ PTHrP) receptor and produce anabolic and catabolic effects in bone. To investigate postreceptor mechanisms of action, MC3T3-E1 cells were induced to differentiate to optimize PTH-1 receptor expression, and differentiated MC3T3-E1 cells were treated with varying doses of PTH (1-34) for 1 h. Northern blot analysis revealed a dose-depen- dent stimulation of steady state c-fos messenger RNA (mRNA), with measurable expression at doses as low as 1 pM PTH. The time course of c-fos mRNA induction was rapid, with peak levels detected at 30 - 45 min. Increased steady state c-fos mRNA was due to increased transcription of the c-fos gene as demonstrated by nuclear run-on assays and was dependent on the temporal differentiation state of the MC3T3-E1 cells. Stimulation of c-fos mRNA was induced exclusively by N-terminal PTH and PTHrP (which is also responsible for cAMP activation), and did not occur with PTH (7-34), (53- 84), or PTHrP (107-139). The effects of PTH (1-34) on c-fos stimulation were de- pendent on intracellular cAMP. Forskolin (a guanine-nucleotide- binding protein (Ga) agonist) stimulated c-fos mRNA, whereas 9- (tetrahydro-2-furyl) adenine (THFA) (a cAMP antagonist), 1,9 dideoxyforskolin (a cAMP independent analog of forskolin), and phor- bol 12-myristate 13-acetate (a protein kinase C activator) did not. Furthermore, THFA inhibited the ability of PTH (1-34) to stimulate c-fos mRNA in a time-dependent manner. These findings indicate that c-fos is transcriptionally regulated by PTH (1-34) in osteoblastic cells, and that cAMP is a mediator of PTH-stimulated c-fos induction. Sev- eral known bone-associated proteins contain DNA binding sites in their promoter regions that recognize c-fos in conjunction with c-jun (AP-1 sites). Consequently, the induction of c-fos by PTH (1-34) in osteoblastic cells may be a sensitive indicator of PTH effects in vitro and in vivo, and provide valuable information regarding mechanisms of PTH action in bone. (Endocrinology 138: 5427-5433, 1997)

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