GLUCOCORTICOID REGULATION OF INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-3

Short stature and decreased growth velocity are prominent features of endogenous and pharmacological glucocorticoid excess in children. Unde rlying processes may involve direct cellular effects or defective gene ration of insulin-like growth factors (IGFs) and/or IGF-binding protei ns (TGFBPs), which modulate IGF-stimulated events and regulate growth. To evaluate potential mechanisms, we investigated the impact of dexam ethasone (dex) on hepatic expression of IGFBP-3, the major carrier pro tein for IGFs. Using cocultured hepatic parenchymal and nonparenchymal cells, dex at 10(-8) and 10(-6) M decreased IGFBP-3 secretion by 67 /- 9% and 73 +/- 9%, respectively (both P < 0.05 vs. no dex). In a sep arate experiment, IGFBP-3 messenger RNA (mRNA) expression was decrease d by 84 +/- 2% and 75 +/- 2% (both P < 0.05 vs. no dex). In combined s tudies, levels of IGFBP-3 protein in conditioned medium were strongly correlated with the abundance of IGFBP-3 mRNA (r = 0.75; P < 0.01), co nsistent with regulation at a pretranslational level. After inhibition of transcription, levels of IGFBP-3 mRNA decreased 85% and 86% over 2 4 h in cells cultured in 10(-6) M and no dex, respectively; the t1/2 w as 13.6 h at 10(-6) M and 12.6 h with no dex, indicating that dex had no effect on IGFBP-3 mRNA stability. To evaluate transcriptional effec ts, the rate of IGFBP-3 gene transcription was measured by incorporati on of [alpha-P-32]UTP into preinitiated message in isolated nuclei and fell 78% after the addition of 10(-6) M dex for 48 h (compared to cel ls cultured in 10(-9) at dex), an inhibition of a magnitude similar to the effects on protein release and mRNA abundance. We conclude that d ex may reduce the production of IGFBP-3 by inhibiting IGFBP-3 gene tra nscription.