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Dickkopf-1, an Inhibitor of Wnt Signaling, Is Regulated by Progesterone in Human Endometrial Stromal Cells

Department of Obstetrics, Gynecology, and Reproductive Sciences (S.T., M.T.O., A.E.H., L.C.G.), University of California, San Francisco, San Francisco, California 94143-0132; Department of Pharmacokinetics, Pharmacodynamics, and Bioanalytical Sciences (N.L.J.), Genentech Inc., South San Francisco, California 94080; and Department of Obstetrics and Gynecology (E.S.), Zagreb University School of Medicine, Zagreb 10000, Croatia

Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., M.Sc., Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 505 Parnassus Avenue M1496, San Francisco, California 94143-0132. E-mail: giudice{at}obgyn.ucsf.edu.

Context: Some members of the Wnt family, including ligands, receptors, inhibitors, and signaling components, are expressed in human endometrium. Dickkopf-1 (Dkk-1), a potent inhibitor of the Wnt signaling pathway, was recently found to be up-regulated in decidualizing endometrial stromal cells during the secretory phase of the menstrual cycle, suggesting regulation by progesterone.

Objectives: To test the hypothesis that progesterone regulates Dkk-1 expression in human endometrial stromal cells, we investigated the following effects on stromal cell expression of Dkk-1 mRNA and protein: decidualizing stimuli (progesterone or cAMP), RU486 (an inhibitor of progesterone action), and withdrawal of progesterone.

Results: Short-term treatment (up to 72 h, which corresponds to the full decidualized phenotype in response to cAMP and an early response to progesterone) did not reveal regulation of Dkk-1 mRNA or protein by cAMP but did show induction of Dkk-1 expression when the cells were treated with progesterone, an effect that was blocked by RU486. In long-term cultures (from 14 to 23 d, which corresponds to the full decidualized phenotype in response to progesterone), a significant increase in Dkk-1 mRNA and protein production was observed. Addition of RU486 or withdrawal of progesterone after long-term decidualization resulted in a decrease of Dkk-1 mRNA and protein to control levels. Estradiol alone had no effect on stromal Dkk-1 expression.

Conclusions: These data strongly support regulation by progesterone of Dkk-1 mRNA synthesis and protein expression in human endometrial stromal cells and that the response is specific for progesterone and independent of cAMP and estradiol.

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