Endocrinology, Vol 136, 1928-1933, Copyright © 1995 by Endocrine Society

ARTICLES

Glucocorticoid regulation of insulin-like growth factor-binding protein- 3

BC Villafuerte, BL Koop, CI Pao and LS Phillips
Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Short stature and decreased growth velocity are prominent features of endogenous and pharmacological glucocorticoid excess in children. Underlying processes may involve direct cellular effects or defective generation of insulin-like growth factors (IGFs) and/or IGF-binding proteins (IGFBPs), which modulate IGF-stimulated events and regulate growth. To evaluate potential mechanisms, we investigated the impact of dexamethasone (dex) on hepatic expression of IGFBP-3, the major carrier protein 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 separate experiment, IGFBP-3 messenger RNA (mRNA) expression was decreased by 84 +/- 2% and 75 +/- 2% (both P < 0.05 vs. no dex). In combined studies, levels of IGFBP-3 protein in conditioned medium were strongly correlated with the abundance of IGFBP-3 mRNA (r = 0.75; P < 0.01), consistent with regulation at a pretranslational level. After inhibition of transcription, levels of IGFBP-3 mRNA decreased 85% and 86% over 24 h in cells cultured in 10(-6) M and no dex, respectively; the t1/2 was 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 effects, the rate of IGFBP-3 gene transcription was measured by incorporation of [alpha-32P]UTP into preinitiated message in isolated nuclei and fell 78% after the addition of 10(-6) M dex for 48 h (compared to cells cultured in 10(-9) M dex), an inhibition of a magnitude similar to the effects on protein release and mRNA abundance. We conclude that dex may reduce the production of IGFBP-3 by inhibiting IGFBP-3 gene transcription.

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