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Time- and Dose-Related Interactions between Glucocorticoid and Cyclic Adenosine 3',5'-Monophosphate on CCAAT/Enhancer-Binding Protein-Dependent Insulin-Like Growth Factor I Expression by Osteoblasts¹

Department of Surgery, Plastic Surgery Section, Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Thomas L. McCarthy, Ph.D., Department of Surgery, Plastic Surgery Section, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208041, New Haven, Connecticut 06520-8041. E-mail: thomas.mccarthy{at}yale.edu

Glucocorticoid has complex effects on osteoblasts. Several of these changes appear to be related to steroid concentration, duration of exposure, or specific effects on growth factor expression or activity within bone. One important bone growth factor, insulin-like growth factor I (IGF-I), is induced in osteoblasts by hormones such as PGE₂ that increase intracellular cAMP levels. In this way, PGE₂ activates transcription factor CCAAT/enhancer-binding protein- (C/EBP) and enhances its binding to a specific control element found in exon 1 in the IGF-I gene. Our current studies show that preexposure to glucocorticoid enhanced C/EBP and C/EBPß expression by osteoblasts and thereby potentiated IGF-I gene promoter activation in response to PGE₂. Importantly, this directly contrasts with inhibitory effects on IGF-I expression that result from sustained or pharmacologically high levels of glucocorticoid exposure. Consistent with the stimulatory effect of IGF-I on bone protein synthesis, pretreatment with glucocorticoid sensitized osteoblasts to PGE₂, and in this context significantly enhanced new collagen and noncollagen protein synthesis. Therefore, pharmacological levels of glucocorticoid may reduce IGF-I expression by osteoblasts and cause osteopenic disease, whereas physiological transient increases in glucocorticoid may permit or amplify the effectiveness of hormones that regulate skeletal tissue integrity. These events appear to converge on the important role of C/EBP and C/EBPß on IGF-I expression by osteoblasts.

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