This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lockwood, C. J. Articles by Schatz, F. Search for Related Content PubMed PubMed Citation Articles by Lockwood, C. J. Articles by Schatz, F.

Matrix Metalloproteinase and Matrix Metalloproteinase Inhibitor Expression in Endometrial Stromal Cells during Progestin-Initiated Decidualization and Menstruation-Related Progestin Withdrawal¹

The Department of Obstetrics and Gynecology, New York University Medical Center, New York, New York 10016

Address all correspondence and requests for reprints to: Dr. Frederick Schatz, Department of Obstetrics and Gynecology, New York University Medical Center, 550 First Avenue, New York, New York 10016.

Estradiol (E) primes human endometrial stromal cells (HESCs) for the decidualizing effects of progesterone in vivo and in vitro. Matrix metalloproteinase (MMP) expression was evaluated in confluent HESCs incubated in control medium, and in medium supplemented with either E, or the synthetic progestin medroxyprogesterone acetate (P), or E + P. Measurements with a specific ELISA indicated that basal pro-MMP-1 output was unaffected by E, whereas E + P, which induces the expression of several decidualization-related markers, produced a time-dependent inhibition in HESC-secreted levels of pro-MMP-1. Consistent with progestin inhibition of MMP-1 protein expression in the HESCs, P but not E, reduced steady state levels of MMP-1 messenger RNA (mRNA) as determined by Northern analysis. By contrast, mRNA levels for MMP-2 and the MMP inhibitor TIMP-1 were not altered by either P or E. Steroid withdrawal studies indicated that after MMP-1 expression was suppressed by incubation of the HESCs with E + P, 4 days of exposure to the antiprogestin RU 486 (mifepristone) significantly up-regulated MMP-1 levels in the conditioned medium by severalfold compared with cultures maintained in E + P. The change to steroid-free control medium required a more prolonged period of withdrawal to attain up regulatory effects that were comparable with those evoked by RU 486. The ELISA measurements were validated by immunoblot analysis with a specific MMP-1 antibody, which showed corresponding changes in a band at the expected mobility of about 50 kDa. Moreover, Northern analysis revealed parallel changes in MMP-1 mRNA levels, whereas neither MMP-2 nor TIMP-1 mRNA levels were modulated by adding or withdrawing steroids. The contrast between regulated MMP-1 expression and constitutive MMP-2 expression observed in the cultured HESCs is consistent with the demonstrated presence on the MMP-1 promoter of regulatory elements such as AP-1 and PEA-3 that are absent from the MMP-2 promoter. Extrapolation of these in vitro changes in HESCs to in vivo endometrial events suggests that: 1) inhibition of MMP-1 expression by E and progesterone would stabilize the perivascular endometrial ECM to prevent local hemorrhage during endovascular invasion by the implanting trophoblast; 2) enhanced expression of MMP-1 evoked by steroid withdrawal would mediate endometrial ECM degradation leading to sloughing of the functional layer during menstruation.

This article has been cited by other articles:

				C. J. Lockwood, C. Oner, Y. H. Uz, U. A. Kayisli, S. J. Huang, L. F. Buchwalder, W. Murk, E. F. Funai, and F. Schatz Matrix Metalloproteinase 9 (MMP9) Expression in Preeclamptic Decidua and MMP9 Induction by Tumor Necrosis Factor Alpha and Interleukin 1 Beta in Human First Trimester Decidual Cells Biol Reprod, June 1, 2008; 78(6): 1064 - 1072. [Abstract] [Full Text] [PDF]

				T. Nagashima, T. Maruyama, H. Uchida, T. Kajitani, T. Arase, M. Ono, H. Oda, M. Kagami, H. Masuda, S. Nishikawa, et al. Activation of SRC Kinase and Phosphorylation of Signal Transducer and Activator of Transcription-5 Are Required for Decidual Transformation of Human Endometrial Stromal Cells Endocrinology, March 1, 2008; 149(3): 1227 - 1234. [Abstract] [Full Text] [PDF]

				R.D. Catalano, H.O. Critchley, O. Heikinheimo, D.T. Baird, D. Hapangama, J.R.A. Sherwin, D.S. Charnock-Jones, S.K. Smith, and A.M. Sharkey Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium Mol. Hum. Reprod., September 1, 2007; 13(9): 641 - 654. [Abstract] [Full Text] [PDF]

				T. Ishikawa, T. Harada, T. Kubota, and T. Aso Testosterone inhibits matrix metalloproteinase-1 production in human endometrial stromal cells in vitro Reproduction, June 1, 2007; 133(6): 1233 - 1239. [Abstract] [Full Text] [PDF]

				H. N. Jabbour, R. W. Kelly, H. M. Fraser, and H. O. D. Critchley Endocrine Regulation of Menstruation Endocr. Rev., February 1, 2006; 27(1): 17 - 46. [Abstract] [Full Text] [PDF]

				M. Plaisier, P. Koolwijk, R. Hanemaaijer, R. A. Verwey, R. M.F. van der Weiden, E. K.J. Risse, C. Jungerius, F. M. Helmerhorst, and V. W.M. van Hinsbergh Membrane-type matrix metalloproteinases and vascularization in human endometrium during the menstrual cycle Mol. Hum. Reprod., January 1, 2006; 12(1): 11 - 18. [Abstract] [Full Text] [PDF]

				C. J. Lockwood, P. Toti, F. Arcuri, M. Paidas, L. Buchwalder, G. Krikun, and F. Schatz Mechanisms of Abruption-Induced Premature Rupture of the Fetal Membranes: Thrombin-Enhanced Interleukin-8 Expression in Term Decidua Am. J. Pathol., November 1, 2005; 167(5): 1443 - 1449. [Abstract] [Full Text] [PDF]

				V. Vassilev, C. M. Pretto, P. B. Cornet, D. Delvaux, Y. Eeckhout, P. J. Courtoy, E. Marbaix, and P. Henriet Response of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Messenger Ribonucleic Acids to Ovarian Steroids in Human Endometrial Explants Mimics Their Gene- and Phase-Specific Differential Control in Vivo J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5848 - 5857. [Abstract] [Full Text] [PDF]

				C. J. Lockwood, P. Kumar, G. Krikun, S. Kadner, P. Dubon, H. Critchley, and F. Schatz Effects of Thrombin, Hypoxia, and Steroids on Interleukin-8 Expression in Decidualized Human Endometrial Stromal Cells: Implications for Long-Term Progestin-Only Contraceptive-Induced Bleeding J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1467 - 1475. [Abstract] [Full Text] [PDF]

				Y. Noguchi, T. Sato, M. Hirata, T. Hara, K. Ohama, and A. Ito Identification and Characterization of Extracellular Matrix Metalloproteinase Inducer in Human Endometrium during the Menstrual Cycle in Vivo and in Vitro J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6063 - 6072. [Abstract] [Full Text] [PDF]

				T. E. Curry Jr. and K. G. Osteen The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle Endocr. Rev., August 1, 2003; 24(4): 428 - 465. [Abstract] [Full Text] [PDF]

				N. Sakai, T. Maruyama, R. Sakurai, H. Masuda, Y. Yamamoto, A. Shimizu, I. Kishi, H. Asada, S. Yamagoe, and Y. Yoshimura Involvement of Histone Acetylation in Ovarian Steroid-induced Decidualization of Human Endometrial Stromal Cells J. Biol. Chem., May 2, 2003; 278(19): 16675 - 16682. [Abstract] [Full Text] [PDF]

				R. Pilka, C. Whatling, H. Domanski, S. Hansson, P. Eriksson, and B. Casslen Epithelial expression of matrix metalloproteinase-26 is elevated at mid-cycle in the human endometrium Mol. Hum. Reprod., May 1, 2003; 9(5): 271 - 277. [Abstract] [Full Text] [PDF]

				D. K. Hapangama, H. O. D. Critchley, T. A. Henderson, and D. T. Baird Mifepristone-Induced Vaginal Bleeding Is Associated with Increased Immunostaining for Cyclooxygenase-2 and Decrease in Prostaglandin Dehydrogenase in Luteal Phase Endometrium J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5229 - 5234. [Abstract] [Full Text] [PDF]

				S.A. Milne, A. Rakhyoot, T.A. Drudy, S. Brechin, S.C. Riley, and H.O.D. Critchley Co-localization of matrix metalloproteinase-1 and mast cell tryptase in the human uterus Mol. Hum. Reprod., June 1, 2001; 7(6): 559 - 565. [Abstract] [Full Text] [PDF]

				T. E. Curry Jr and K. G. Osteen Cyclic Changes in the Matrix Metalloproteinase System in the Ovary and Uterus Biol Reprod, May 1, 2001; 64(5): 1285 - 1296. [Abstract] [Full Text]

				K. Watanabe, C. A. Kessler, C. J. Bachurski, Y. Kanda, B. D. Richardson, J. Stanek, S. Handwerger, and A. K. Brar Identification of a Decidua-Specific Enhancer on the Human Prolactin Gene with Two Critical Activator Protein 1 (AP-1) Binding Sites Mol. Endocrinol., April 1, 2001; 15(4): 638 - 653. [Abstract] [Full Text]

				V. Jokimaa, S. Oksjoki, H. Kujari, E. Vuorio, and L. Anttila Expression patterns of cathepsins B, H, K, L and S in the human endometrium Mol. Hum. Reprod., January 1, 2001; 7(1): 73 - 78. [Abstract] [Full Text] [PDF]

				N. R. Nayak, H. O. D. Critchley, O. D. Slayden, A. Menrad, K. Chwalisz, D. T. Baird, and R. M. Brenner Progesterone Withdrawal Up-Regulates Vascular Endothelial Growth Factor Receptor Type 2 in the Superficial Zone Stroma of the Human and Macaque Endometrium: Potential Relevance to Menstruation J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3442 - 3452. [Abstract] [Full Text]

				F. C. Denison, S. C. Riley, C. L. Elliott, R. W. Kelly, A. A. Calder, and H. O.D. Critchley The effect of mifepristone administration on leukocyte populations, matrix metalloproteinases and inflammatory mediators in the first trimester cervix Mol. Hum. Reprod., June 1, 2000; 6(6): 541 - 548. [Abstract] [Full Text] [PDF]

				N. R. Keller, E. Sierra-Rivera, E. Eisenberg, and K. G. Osteen Progesterone Exposure Prevents Matrix Metalloproteinase-3 (MMP-3) Stimulation by Interleukin-1{alpha} in Human Endometrial Stromal Cells J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1611 - 1619. [Abstract] [Full Text]

				K. MATSUI, K. TAKEDA, Z.-X. YU, J. VALENCIA, W. D. TRAVIS, J. MOSS, and V. J. FERRANS Downregulation of Estrogen and Progesterone Receptors in the Abnormal Smooth Muscle Cells in Pulmonary Lymphangioleiomyomatosis Following Therapy . An Immunohistochemical Study Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): 1002 - 1009. [Abstract] [Full Text] [PDF]

				J. J. Brosens, N. Hayashi, and J. O. White Progesterone Receptor Regulates Decidual Prolactin Expression in Differentiating Human Endometrial Stromal Cells Endocrinology, October 1, 1999; 140(10): 4809 - 4820. [Abstract] [Full Text]