Insulin-like growth factor I suppresses parathyroid hormone (PTH)/PTH-related protein receptor expression via a mitogen-activated protein kinase pathway in UMR-106 osteoblast-like cells

• Published in: Endocrinology (Philadelphia) 1999-02, Vol.140 (2), p.871-879
• Main Authors: Kawane, T, Horiuchi, N
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Insulin-Like Growth Factor I - pharmacology; Molecular Sequence Data; Osteoblasts - metabolism; Rats; Receptor, Parathyroid Hormone, Type 1; Receptors, Parathyroid Hormone - genetics; Receptors, Parathyroid Hormone - metabolism; RNA, Messenger - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Tumor Cells, Cultured
• ISSN: 0013-7227
• DOI: 10.1210/en.140.2.871

Insulin-like growth factor I (IGF-I) is important in skeletal growth and has been implicated in the maintenance of bone integrity. PTH stimulates bone resorption through the G protein-linked PTH/PTH-related protein (PTHrP) receptor in osteoblasts. Using a heterogeneous nuclear RNA assay and Northern blot analysis, we showed that IGF-I inhibited expression of the gene for PTH/PTHrP receptor in a dose- and time-dependent fashion, but did not alter the stability of the receptor messenger RNA (mRNA) in UMR-106 osteoblast-like cells. IGF-I treatment for 48 h also caused a decrease in the receptor number to 45% of that in controls without affecting receptor affinity and in functional receptor expression to 50-60% of that in controls as measured by PTH-stimulated cAMP production. In MC3T3-E1 murine nontransformed osteoblasts, IGF suppressed receptor mRNA expression dose dependently. In UMR-106 cells, IGF-I induced the mitogen-activated protein (MAP) kinase pathway. The effect of IGF-I was blocked by PD98059, a specific inhibitor of the MAP kinase-activating kinase, but not by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. IGF-I inhibition of PTH/PTHrP receptor mRNA expression in UMR-106 cells was abrogated completely by pretreatment with cycloheximide, an inhibitor of protein synthesis. These findings indicate that IGF-I suppresses gene expression for PTH/PTHrP receptor via the MAP kinase pathway, and this inhibition is required for new protein synthesis in UMR-106 osteoblast-like cells.