Endocrinology, Vol 137, 2375-2382, Copyright © 1996 by Endocrine Society

ARTICLES

Transcriptional regulation of insulin-like growth factor-binding protein-5 by prostaglandin E2 in osteoblast cells

JM Pash and E Canalis
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105, USA.

Insulin-like growth factor (IGF)-binding protein-5 (IGFBP-5) is an autocrine and paracrine factor that modulates the effects of IGFs. We examined the mechanisms that regulate IGFBP-5 synthesis by PGE2 in osteoblast-enriched cells from fetal rat calvaria (Ob cells). PGE2 at 1 microM for 2-8 h increased IGFBP-5 heterogeneous nuclear RNA levels and did not change the half-life of IGFBP-5 messenger RNA in Ob cells, suggesting that PGE2 stimulates IGFBP-5 transcription. To analyze the elements responsible for this effect, regions of the mouse IGFBP-5 promoter from -2695 to +120 bp were ligated into pGL-2-basic and transiently transfected into Ob cells. PGE2 caused a time- and dose- dependent increase in IGFBP-5 promoter activity. Further analysis revealed two potential PGE2-responsive regions in the -2695 to -1470 and the -989 to -332 fragments. The effect of PGE2 on IGFBP-5 messenger RNA and heterogeneous nuclear RNA levels was mimicked by forskolin and inhibited by the PKA inhibitor H-89, suggesting that part of the PGE2 effect was mediated through a cAMP-dependent pathway. H-89 also blocked basal and PGE2-stimulated IGFBP-5 promoter activities. We conclude that PGE2 regulates IGFBP-5 synthesis in Ob cells by transcriptional mechanisms. PKA-dependent pathways account for part of the effect of PGE2 on IGFBP-5 expression. Deletion analysis of the IGFBP-5 promoter suggests the presence of two PGE2-responsive regions.

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