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Transforming Growth Factor-β1 Attenuates Expression of Both the Progesterone Receptor and Dickkopf in Differentiated Human Endometrial Stromal Cells

Medical Research Council Human Reproductive Sciences Unit (N.K., P.T.K.S., R.W.K.), Reproductive and Developmental Sciences (H.O.D.C.), Centre for Reproductive Biology, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; and Institute of Reproductive and Developmental Biology (M.J., J.J.B.), Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS, United Kingdom

Address all correspondence and requests for reprints to: Hilary O. D. Critchley, Reproductive and Developmental Sciences, Centre for Reproductive Biology, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: hilary.critchley{at}ed.ac.uk.

TGFβ1 is thought to be intimately involved in cyclic tissue remodeling and inflammatory events associated with menstruation. Menstruation is initiated by progesterone withdrawal; however, the underlying mechanisms are not well understood. In the present study, we have tested the hypothesis that locally produced TGFβ1 may influence expression of progesterone receptor (PR) or the Wnt antagonist Dickkopf-1 (DKK) with consequential impact on regulation of menstruation. Endometrial stromal cells (ESC) were isolated from endometrial biopsy samples collected from patients undergoing gynecological procedures for benign indications. Treatment of differentiated ESC with TGFβ1 (10 ng/ml) significantly inhibited the expression of mRNAs encoding PR and DKK. TGFβ1 also attenuated the protein expression of PR and secretion of DKK proteins in culture supernatants. Neutralization of endogenous TGFβ1 signaling abolished the TGFβ1-induced effects, significantly increased expression of PR, and increased DKK protein release levels to that of differentiated ESCs, confirming the specificity of the TGFβ1 effect. Additionally, in vitro decidualization of ESCs significantly augmented DKK protein release. Moreover, although TGFβ1 was capable of signaling via the Sma- and mothers against decapentaplegic (MAD)-related protein (SMAD) pathway, the inhibitory effect on DKK was SMAD independent. Conversely, the inhibitory effect of TGFβ1 on PR was dependent on SMAD signal transduction. In conclusion, these results suggest that local TGFβ1 signaling can potentiate progesterone withdrawal by suppressing expression of PR and may coordinate tissue remodeling associated with menstruation by inducing Wnt-signaling via inhibition of DKK, which we found to be up-regulated as a consequence of decidualization of ESCs.

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