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J. Biol. Chem., Vol. 282, Issue 47, 34003-34012, November 23, 2007

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3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts^*

Thomas L. McCarthy¹, Richard B. Hochberg, David C. Labaree, and Michael Centrella²

From the Department of Surgery, Section of Plastic Surgery and the Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520

In addition to reproductive tissue, sex hormones induce transcriptional events in many connective tissue cells, including osteoblasts. Some sex hormone receptor modulators with bone sparing effects selectively target estrogen or androgen receptors, whereas others appear more promiscuous, in part through enzymatic metabolism. Rat osteoblasts express significant oxidative 3-hydroxysteroid dehydrogenase activity, which can convert precursor substrates to potent androgen receptor agonists. Here we show that they also express 3-ketosteroid reductase activity, exemplified by 7-methyl-17-ethynyl-19-norandrostan-5 (10)en-3-one (tibolone) conversion to potent estrogen receptor agonists. Conversion was rapid and quantitative, with 3-hydroxytibolone as the primary metabolite. Consistently, tibolone induced estrogen receptor -dependent gene promoter activity through cis-acting estrogen response elements, increased the stimulatory effect of TGF- on Smad-dependent gene promoter activity, and enhanced prostaglandin E2-induced activity of transcription factor Runx2. Rat osteoblasts express the 3-ketosteroid reductase AKR1C9, an aldo-keto reductase gene family member. Exposure to prostaglandin E2 increased AKR1C9 gene promoter activity and mRNA expression. AKR1C9 promoter activity was also enhanced by overexpression of protein kinase A catalytic subunit or transcription factor C/EBP, and the effect of PGE2 was reduced by dominant negative C/EBP competition or C/EBP antisense expression. Moreover, prostaglandin E2 increased the amount of functional endogenous nuclear C/EBP that could bind specifically to a distinct domain 1.8-kb upstream from the start site of AKR1C9 transcription. In summary, in addition to 3-hydroxysteroid dehydrogenase, rat osteoblasts express significant and regulatable 3-ketosteroid reductase activity. Through these enzymes, they may selectively metabolize precursor compounds into potent steroid receptor agonists locally within bone.

Received for publication, September 7, 2007

^* This work was supported by National Institutes of Health Research Awards AR39201, CA37799, and HL61432. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence may be addressed: 333 Cedar St., MS 208041 New Haven, CT 06520-8041. Tel.: 203-795-3120; E-mail: thomas.mccarthy{at}yale.edu. ² To whom correspondence may be addressed: 333 Cedar St., MS 208041 New Haven, CT 06520-8041. Tel.: 203-785-4927; E-mail: michael.centrella{at}yale.edu.

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