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Endocrinology Vol. 139, No. 4 2048-2057
Copyright © 1998 by The Endocrine Society

ARTICLES

Estrogen Receptor-{alpha} Is Developmentally Regulated during Osteoblast Differentiation and Contributes to Selective Responsiveness of Gene Expression

Peter V. N. Bodine, Ruth A. Henderson, Jack Green, Michael Aronow, Thomas Owen, Gary S. Stein, Jane B. Lian and Barry S. Komm

Women’s Health Research Institute, Wyeth-Ayerst (P.V.N.B., R.A.H., B.S.K.), Radnor, Pennsylvania 19087; and the Department of Cell Biology, University of Massachusetts Medical Center (J.G., M.A., T.O., G.S.S., J.B.L.), Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Dr. Peter V. N. Bodine, Women’s Health Research Institute, Wyeth-Ayerst Research, 145 King of Prussia Road, Radnor, Pennsylvania 19087. E-mail: bodinep{at}war.wyeth.com

Estrogen responsiveness of bone is a fundamental regulatory mechanism operative in skeletal homeostasis. We examined the expression of estrogen receptor-{alpha} (ER) messenger RNA (mRNA) in cultured rat calvarial-derived osteoblasts during progressive development of the osteoblast phenotype. Levels of ER message were compared with the expression of traditional osteoblastic markers that have been mapped throughout the differentiation process of these cells. ER transcripts, measured using semiquantitative RT-PCR analysis, were expressed at low levels in early stage proliferating osteoblasts and increased at confluence upon initial expression of bone cell phenotypic genes. A 23-fold up-regulation of ER mRNA expression coincided with the initiation of alkaline phosphatase activity (day 8). ER mRNA levels progressively increased 70-fold, reaching a maximum level on days 22–25 in fully differentiated osteoblasts when osteocalcin expression peaked, but declined precipitously by day 32 in osteocytic cells. Analysis of RNA isolated directly from rat calvaria confirmed these in vitro results and demonstrated that ER message levels become more abundant postnatally as bone becomes more mineralized. We also examined the responsiveness of osteoblasts to 17ß-estradiol (17ß-E2) at two periods of maturation: the nodule-forming stage (day 14) and the late mineralization stage (day 30). Estradiol suppressed the levels of alkaline phosphatase, osteocalcin, osteonectin, and ER mRNAs on day 14, but up-regulated these messages on day 30. In contrast, 17ß-E2 treatment regulated the steady state levels of transforming growth factor-ß1 and type I procollagen mRNAs only in the late mineralization stage, whereas histone H4 message was unaffected by the steroid at either stage of differentiation. Thus, the observed developmental expression of ER mRNA correlates with progressive osteoblast differentiation and may be a contributing factor to differential regulation of bone cell gene expression by 17ß-E2.




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