Cortisol inhibits the synthesis of insulin-like growth factor-binding protein-5 in bone cell cultures by transcriptional mechanisms.
Glucocorticoids inhibit the synthesis of insulin-like growth factor-binding protein-5 (IGFBP-5) in osteoblasts, but the mechanisms involved are unknown. IGFBP-5 stimulates bone cell growth, and its inhibition by glucocorticoids may be relevant to the action of this binding protein on bone formation. We tested the effects of cortisol on IGFBP-5 expression in cultures of osteoblast-enriched cells from fetal rat calvariae (Ob cells). Cortisol decreased IGFBP-5 polypeptide levels in the extracellular matrix and caused a time- and dose-dependent decrease in IGFBP-5 mRNA. IGFBP-5 transcripts were markedly decreased by cycloheximide, and further suppressive effects of cortisol could not be determined. Cortisol did not modify the decay of IGFBP-5 mRNA in transcriptionally arrested Ob cells. Cortisol decreased IGFBP-5 hnRNA, the rate of IGFBP-5 transcription, and the activity of the murine IGFBP-5 promoter by 35% in transient transfection experiments. Deletion analysis showed that the region responsive to cortisol is from base pairs -70 to +22, and E-box-binding proteins or c-Myb-related nuclear factors may be involved in its regulation. In conclusion, cortisol inhibits IGFBP-5 transcription in Ob cells through the Myb-binding domain. This effect may be partly responsible for the effect of glucocorticoids on bone formation.
Gabbitas
B
B
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105, USA.
Pash
J M
JM
Delany
A M
AM
Canalis
E
E
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D001842:Bone and Bones / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D006854:Hydrocortisone / Q000494:pharmacology*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015183:Restriction Mapping; D017384:Sequence Deletion; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D017931:DNA Primers; D018975:Insulin-Like Growth Factor Binding Protein 5; D012333:RNA, Messenger; D003513:Cycloheximide; D006854:Hydrocortisone