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Volume 272, Number 29, Issue of July 18, 1997 pp. 18132-18139
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

17-Estradiol Potently Suppresses cAMP-induced Insulin-like Growth Factor-I Gene Activation in Primary Rat Osteoblast Cultures

(Received for publication, February 12, 1997, and in revised form, May 16, 1997)

Thomas L. McCarthy , Changhua Ji , Hong Shu , Sandra Casinghino , Kristina Crothers , Peter Rotwein ^¶ and Michael Centrella

From the  Yale University School of Medicine, Section of Plastic Surgery, New Haven, Connecticut 06520-8041 and the ^¶ Division of Molecular Medicine, Oregon Health Sciences University, Portland, Oregon 97201-3098

Insulin-like growth factor-I (IGF-I) is a key factor in bone remodeling. In osteoblasts, IGF-I synthesis is enhanced by parathyroid hormone and prostaglandin E₂ (PGE₂) through cAMP-activated protein kinase. In rats, estrogen loss after ovariectomy leads to a rise in serum IGF-I and an increase in bone remodeling, both of which are reversed by estrogen treatment. To examine estrogen-dependent regulation of IGF-I expression at the molecular level, primary fetal rat osteoblasts were co-transfected with the estrogen receptor (hER, to ensure active ER expression), and luciferase reporter plasmids controlled by promoter 1 of the rat IGF-I gene (IGF-I P1), used exclusively in these cells. As reported, 1 µM PGE₂ increased IGF-I P1 activity by 5-fold. 17-Estradiol alone had no effect, but dose-dependently suppressed the stimulatory effect of PGE₂ by up to 90% (ED₅₀ ~0.1 nM). This occurred within 3 h, persisted for at least 16 h, required ER, and appeared specific, since 17-estradiol was 100-300-fold less effective. By contrast, 17-estradiol stimulated estrogen response element (ERE)-dependent reporter expression by up to 10-fold. 17-Estradiol also suppressed an IGF-I P1 construct retaining only minimal promoter sequence required for cAMP-dependent gene activation, but did not affect the 60-fold increase in cAMP induced by PGE₂. There is no consensus ERE in rat IGF-I P1, suggesting novel downstream interactions in the cAMP pathway that normally enhances IGF-I expression in skeletal cells. To explore this, nuclear extract from osteoblasts expressing hER were examined by electrophoretic mobility shift assay using the atypical cAMP response element in IGF-I P1. Estrogen alone did not cause DNA-protein binding, while PGE₂ induced a characteristic gel shift complex. Co-treatment with both hormones caused a gel shift greatly diminished in intensity, consistent with their combined effects on IGF-I promoter activity. Nonetheless, hER did not bind IGF-I cAMP response element or any adjacent sequences. These results provide new molecular evidence that estrogen may temper the biological effects of hormones acting through cAMP to regulate skeletal IGF-I expression and activity.

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