Cortisol enhances the transcription of insulin-like growth factor-binding protein-6 in cultured osteoblasts.
Previous work indicate that glucocorticoids inhibit the synthesis of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IG-FBP-3), -4, and -5, but not IGFBP-6, in osteoblast cultures. IGFBP-6 binds IGF-II with high affinity and prevents IGF-II-mediated effects. As IGF-II is present at high concentrations in bone, we postulate that glucocorticoids may regulate IGF-II by altering IGFBP-6 synthesis. We tested the expression of IGFBP-6 in cultures of osteoblast-enriched cells from 22-day-old fetal rat calvariae (Ob cells). Treatment of Ob cells with cortisol caused a time- and dose-dependent increase in IGFBP-6 messenger RNA levels, as determined by Northern blot analysis. The effect was maximal after 48 h of treatment and observed with cortisol concentrations of 10 nM to 1 microM. Treatment with cortisol also increased IGFBP-6 polypeptide levels in the medium, as determined by Western immunoblot analysis. Cycloheximide at 3.6 microM decreased IGFBP-6 transcripts and prevented the stimulatory effect of cortisol. Cortisol did not modify the decay of IGFBP-6 messenger RNA in transcriptionally arrested Ob cells. In addition, cortisol increased the rate of IGFBP-6 transcription, as determined by nuclear run-on assays. In conclusion, cortisol stimulates IGFBP-6 expression in Ob cells by transcriptional mechanisms. As IGFBP-6 binds to and prevents the effect of IGF-II, its increased synthesis could be relevant to the inhibitory actions of cortisol in bone.
Gabbitas
B
B
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105, USA.
Canalis
E
E
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001842:Bone and Bones / Q000196:embryology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006854:Hydrocortisone / Q000494:pharmacology*; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
D018976:Insulin-Like Growth Factor Binding Protein 6; D012333:RNA, Messenger; D003513:Cycloheximide; D006854:Hydrocortisone