Transcriptional repression of insulin-like growth factor I by glucocorticoids in rat bone cells.
Insulin-like growth factor I (IGF-I) is an abundant autocrine and paracrine growth factor secreted by osteoblasts. It promotes osteoblast proliferation and expression of their differentiated phenotype. Glucocorticoids decrease IGF-I production by osteoblasts, which may mediate some actions of the steroid on bone in both normal and pathological states. The mechanisms by which the glucocorticoid cortisol down-regulates IGF-I transcripts were explored using cultures of osteoblast-enriched cells derived from fetal rat calvaria (Ob cells). Repression of IGF-I transcripts was apparent after 8 h of treatment, was sustained for at least 24 h, and was not altered by cotreatment with cycloheximide. Cortisol did not alter the stability of IGF-I messenger RNAs in transcriptionally arrested Ob cells. Cortisol decreased IGF-I heterogeneous nuclear RNA and gene transcription, as determined by reverse transcription-linked polymerase chain reaction and nuclear run-on assay, respectively. Transient transfection of Ob cells with constructs containing portions of the rat IGF-I exon 1 promoter and 5'-flanking DNA linked to the reporter gene luciferase were performed to determine glucocorticoid-responsive region of the rat IGF-I exon 1 promoter was localized to 34 to 192 relative to the first start site of transcription. In conclusion, cortisol inhibits the transcription of IGF-I in osteoblasts, an effect that may be relevant to the actions of cortisol in bone.
Delany
A M
AM
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105, USA.
Canalis
E
E
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005091:Exons; D005938:Glucocorticoids / Q000494:pharmacology*; D006854:Hydrocortisone / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012332:RNA, Heterogeneous Nuclear / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D005938:Glucocorticoids; D012332:RNA, Heterogeneous Nuclear; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D006854:Hydrocortisone