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Semin Reprod Med 2003; 21(2): 155-164
DOI: 10.1055/s-2003-41322
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Matrix Metalloproteinases and Endometriosis

Kevin G. Osteen, Grant R. Yeaman, Kaylon L. Bruner-Tran
  • Women's Reproductive Health Research Center Department of Obstetrics Gynecology, Vanderbilt University School of Medicine Nashville, Tennessee
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Publication History

Publication Date:
14 August 2003 (online)

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ABSTRACT

Retrograde menstruation represents a plausible explanation for the development of most cases of endometriosis; nevertheless, additional factors must contribute to the development of disease in only 10 to 20% of women. The discriminating factor(s) in determining the development of active endometriosis probably involves a complex array of potentially interactive influences including steroid exposure, immunological disturbances, genetic predisposition, and, perhaps, environmental toxin exposure. Matrix metalloproteinases (MMPs), enzymes that mediate normal tissue turnover including endometrial breakdown at menstruation, appear to be involved in the invasive establishment of the disease. In addition, several MMPs appear to be inappropriately expressed in the endometrium of women with this disease in association with a reduced sensitivity to progesterone. Altered regulation of endometrial MMP expression in response to steroids may represent a mechanism linking the invasive potential of refluxed endometrium to the establishment of this disease only in certain women.

KEYWORDS

Endometriosis - progesterone - estrogen - matrix metalloproteinases - proinflammatory cytokines

REFERENCES

  • 1 Sampson J. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity.  Am J Obstet Gynecol . 1927;  14 422-469
    CrossrefPubMedGoogle Scholar
  • 2 Liu D T, Hitchcock A. Endometriosis: its association with retrograde menstruation, dysmenorrhoea and tubal pathology.  Br J Obstet Gynaecol . 1986;  93 859-862
    CrossrefPubMedGoogle Scholar
  • 3 TeLinde R, Scott R. Experimental endometriosis.  Am J Obstet Gynecol . 1950;  60 1147-1173
    PubMedGoogle Scholar
  • 4 Ridley J, Edwards I. Experimental endometriosis in the human.  Am J Obstet Gynecol . 1958;  76 783-790
    PubMedGoogle Scholar
  • 5 Cramer D W, Wilson E, Stillman R J. et al . The relation of endometriosis to menstrual characteristics, smoking, and exercise.  JAMA . 1986;  255 1904-1908
    CrossrefPubMedGoogle Scholar
  • 6 Cramer D W, Missmer S A. The epidemiology of endometriosis.  Ann NY Acad Sci . 2002;  955 11-406
    PubMedGoogle Scholar
  • 7 Dmowski W P, Steele R W, Baker G F. Deficient cellular immunity in endometriosis.  Am J Obstet Gynecol . 1981;  141 377-383
    PubMedGoogle Scholar
  • 8 Steele R W, Dmowski W P, Marmer D J. Immunologic aspects of human endometriosis.  Am J Reprod Immunol . 1984;  6 33-36
    PubMedGoogle Scholar
  • 9 Rier S E, Yeaman G R. Immune aspects of endometriosis: relevance of the uterine mucosal immune system.  Semin Reprod Endocrinol . 1997;  15 209-220
    PubMedGoogle Scholar
  • 10 Simpson J L, Bischoff F Z. Heritability and molecular genetic studies of endometriosis.  Ann NY Acad Sci . 2002;  955 239-406
    PubMedGoogle Scholar
  • 11 Kennedy S. The genetics of endometriosis.  Eur J Obstet Gynecol Reprod Biol . 1999;  82 129-133
    CrossrefPubMedGoogle Scholar
  • 12 Bruner-Tran K L, Rier S E, Eisenberg E, Osteen K G. The potential role of environmental toxins in the pathophysiology of endometriosis.  Gynecol Obstet Invest . 1999;  48 (suppl 1) 45-56
    CrossrefPubMedGoogle Scholar
  • 13 Sternlicht M D, Werb Z. How matrix metalloproteinases regulate cell behavior.  Annu Rev Cell Dev Biol . 2001;  17 463-516
    CrossrefPubMedGoogle Scholar
  • 14 Rodgers W H, Osteen K G, Matrisian L M. et al . Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle.  Am J Obstet Gynecol . 1993;  168 253-260
    PubMedGoogle Scholar
  • 15 Rodgers W H, Matrisian L M, Giudice L C. et al . Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones.  J Clin Invest . 1994;  94 946-953
    CrossrefPubMedGoogle Scholar
  • 16 Osteen K G, Rodgers W H, Gaire M. et al . Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium.  Proc Natl Acad Sci U S A . 1994;  91 10129-10133
    Google Scholar
  • 17 Schatz F, Papp C, Toth-Pal E, Lockwood C J. Ovarian steroid-modulated stromelysin-1 expression in human endometrial stromal and decidual cells.  J Clin Endocrinol Metab . 1994;  78 1467-1472
    CrossrefPubMedGoogle Scholar
  • 18 Bruner-Tran K, Eisenberg E, Yeaman G. et al . Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice.  J Clin Endocrinol Metab . 2002;  87 4782-4791
    CrossrefPubMedGoogle Scholar
  • 19 Bruner K L, Matrisian L M, Rodgers W H, Gorstein F, Osteen K G. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice.  J Clin Invest . 1997;  99 2851-2857
    CrossrefPubMedGoogle Scholar
  • 20 Curry Jr E T, Osteen K G. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus.  Biol Reprod . 2001;  64 1285-1296
    PubMedGoogle Scholar
  • 21 Osteen K G, Bruner K L, Sharpe-Timms K L. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis.  Semin Reprod Endocrinol . 1996;  14 247-255
    PubMedGoogle Scholar
  • 22 Gazvani R, Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis.  Reproduction . 2002;  123 217-226
    CrossrefPubMedGoogle Scholar
  • 23 Schroen D J, Brinckerhoff C E. Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms.  Gene Expr . 1996;  6 197-207
    PubMedGoogle Scholar
  • 24 Kushner P J, Agard D A, Greene G L. et al . Estrogen receptor pathways to AP-1.  J Steroid Biochem Mol Biol . 2000;  74 311-317
    CrossrefPubMedGoogle Scholar
  • 25 Teyssier C, Belguise K, Galtier F, Chalbos D. Characterization of the physical interaction between estrogen receptor alpha and JUN proteins.  J Biol Chem . 2001;  276 36361-36369
    CrossrefPubMedGoogle Scholar
  • 26 Benbow U, Brinckerhoff C E. The AP-1 site and MMP gene regulation: what is all the fuss about?.  Matrix Biol . 1997;  15 519-526
    CrossrefPubMedGoogle Scholar
  • 27 Rudolph-Owen L A, Slayden O D, Matrisian L M, Brenner R M. Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients.  Biol Reprod . 1998;  59 1349-1359
    CrossrefPubMedGoogle Scholar
  • 28 Bamberger A M, Bamberger C M, Gellersen B, Schulte H M. Modulation of AP-1 activity by the human progesterone receptor in endometrial adenocarcinoma cells.  Proc Natl Acad Sci U S A . 1996;  93 6169-6174
    CrossrefPubMedGoogle Scholar
  • 29 Salmi A, Ammala M, Rutanen E M. Proto-oncogenes c-jun and c-fos are down-regulated in human endometrium during pregnancy: relationship to oestrogen receptor status.  Mol Hum Reprod . 1996;  2 979-984
    PubMedGoogle Scholar
  • 30 Kirkland J L, Murthy L, Stancel G M. Progesterone inhibits the estrogen-induced expression of c-fos messenger ribonucleic acid in the uterus.  Endocrinology . 1992;  130 3223-3230
    CrossrefPubMedGoogle Scholar
  • 31 Osteen K G, Bruner-Tran K L, Ong D, Eisenberg E. Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis.  Ann NY Acad Sci . 2002;  955 139-406
    PubMedGoogle Scholar
  • 32 Osteen K G, Keller N R, Feltus F A, Melner M H. Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium.  Gynecol Obstet Invest . 1999;  48 (suppl 1) 2-13
    CrossrefPubMedGoogle Scholar
  • 33 Matrisian L M. Matrix metalloproteinase gene expression.  Ann NY Acad Sci . 1994;  732 42-50
    PubMedGoogle Scholar
  • 34 Campbell C E, Flenniken A M, Skup D, Williams B R. Identification of a serum- and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene.  J Biol Chem . 1991;  266 7199-7206
    PubMedGoogle Scholar
  • 35 Edwards D R, Rocheleau H, Sharma R R. et al . Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription.  Biochim Biophys Acta . 1992;  1171 41-55
    PubMedGoogle Scholar
  • 36 Logan S K, Garabedian M J, Campbell C E, Werb Z. Synergistic transcriptional activation of the tissue inhibitor of metalloproteinases-1 promoter via functional interaction of AP-1 and Ets-1 transcription factors.  J Biol Chem . 1996;  271 774-782
    CrossrefPubMedGoogle Scholar
  • 37 De Clerck A Y, Darville M I, Eeckhout Y, Rousseau G G. Characterization of the promoter of the gene encoding human tissue inhibitor of metalloproteinases-2 (TIMP-2).  Gene . 1994;  139 185-191
    CrossrefPubMedGoogle Scholar
  • 38 Hammani K, Blakis A, Morsette D. et al . Structure and characterization of the human tissue inhibitor of metalloproteinases-2 gene.  J Biol Chem . 1996;  271 25498-25505
    CrossrefPubMedGoogle Scholar
  • 39 Wick M, Haronen R, Mumberg D. et al . Structure of the human TIMP-3 gene and its cell cycle-regulated promoter.  Biochem J . 1995;  311( Pt 2) 549-554
    PubMedGoogle Scholar
  • 40 Apte S S, Mattei M G, Olsen B R. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22.  Genomics . 1994;  19 86-90
    CrossrefPubMedGoogle Scholar
  • 41 Riley S C, Leask R, Denison F C. et al . Secretion of tissue inhibitors of matrix metalloproteinases by human fetal membranes, decidua and placenta at parturition.  J Endocrinol . 1999;  162 351-359
    CrossrefPubMedGoogle Scholar
  • 42 Salamonsen L A, Butt A R, Hammond F R, Garcia S, Zhang J. Production of endometrial matrix metalloproteinases, but not their tissue inhibitors, is modulated by progesterone withdrawal in an in vitro model for menstruation.  J Clin Endocrinol Metab . 1997;  82 1409-1415
    CrossrefPubMedGoogle Scholar
  • 43 Bruner K L, Rodgers W H, Gold L I. et al . Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium.  Proc Natl Acad Sci USA . 1995;  92 7362-7366
    CrossrefPubMedGoogle Scholar
  • 44 Huang H Y, Wen Y, Irwin J C. et al . Cytokine-mediated regulation of 92-kilodalton type IV collagenase, tissue inhibitor or metalloproteinase-1 (TIMP-1), and TIMP-3 messenger ribonucleic acid expression in human endometrial stromal cells.  J Clin Endocrinol Metab . 1998;  83 1721-1729
    CrossrefPubMedGoogle Scholar
  • 45 Spuijbroek M D, Dunselman G A, Menheere P P, Evers J L. Early endometriosis invades the extracellular matrix.  Fertil Steril . 1992;  58 929-933
    PubMedGoogle Scholar
  • 46 Eyster K M, Boles A L, Brannian J D, Hansen K A. DNA microarray analysis of gene expression markers of endometriosis.  Fertil Steril . 2002;  77 38-42
    CrossrefPubMedGoogle Scholar
  • 47 Kao L C, Tulac S, Imani B. et al . Expression profile comparisons in eutopic endometrium between women with and without endometriosis during the window of implantation.  Fertil Steril . 2002;  77 S27-S28
    PubMedGoogle Scholar
  • 48 Zhang J, Salamonsen L A. In vivo evidence for active matrix metalloproteinases in human endometrium supports their role in tissue breakdown at menstruation.  J Clin Endocrinol Metab . 2002;  87 2346-2351
    CrossrefPubMedGoogle Scholar
  • 49 Vincent A J, Malakooti N, Zhang J. et al . Endometrial breakdown in women using Norplant is associated with migratory cells expressing matrix metalloproteinase-9 (gelatinase B).  Hum Reprod . 1999;  14 807-815
    CrossrefPubMedGoogle Scholar
  • 50 Skinner J L, Riley S C, Gebbie A E, Glasier A F, Critchley H O. Regulation of matrix metalloproteinase-9 in endometrium during the menstrual cycle and following administration of intrauterine levonorgestrel.  Hum Reprod . 1999;  14 793-799
    CrossrefPubMedGoogle Scholar
  • 51 Maatta M, Soini Y, Liakka A, Autio-Harmainen H. Localization of MTI-MMP, TIMP-1, TIMP-2, and TIMP-3 messenger RNA in normal, hyperplastic, and neoplastic endometrium. Enhanced expression by endometrial adenocarcinomas is associated with low differentiation.  Am J Clin Pathol . 2000;  114 402-411
    PubMedGoogle Scholar
  • 52 Zhang J, Salamonsen L A. Tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3 in human endometrium during the menstrual cycle.  Mol Hum Reprod . 1997;  3 735-741
    CrossrefPubMedGoogle Scholar
  • 53 Osteen K G. The endocrinology of decidualization. In: Bazer F, ed. The Endocrinology of Pregnancy Totowa, NJ: Humana Press 1998: 541-663
    Google Scholar
  • 54 Kamat B, Isaacson P. The immunocytochemical distribution of leukocytic subpopulations in human endometrium.  Am J Pathol . 1987;  127 66-73
    PubMedGoogle Scholar
  • 55 Bonatz G, Hansmann M L, Buchholz F. et al . Macrophage- and lymphocyte-subtypes in the endometrium during different phases of the ovarian cycle.  Int J Gynaecol Obstet . 1992;  37 29-36
    CrossrefPubMedGoogle Scholar
  • 56 Loke Y W, King A. Human Implantation: Cell Biology and Immunology. New York: Cambridge University Press; 1996
    Google Scholar
  • 57 Yeaman G, Guyre P, Fanger M. et al . Unique CD8+ T cell-rich lymphoid aggregates in human uterine endometrium.  J Leukoc Biol . 1997;  61 427-435
    PubMedGoogle Scholar
  • 58 Vincent A J, Salamonsen L A. The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives.  Hum Reprod . 2000;  15 (suppl 3) 135-143
    CrossrefPubMedGoogle Scholar
  • 59 Tabibzadeh S. Signals and molecular pathways involved in apoptosis, with special emphasis on human endometrium.  Hum Reprod Update . 1995;  1 303-323
    CrossrefPubMedGoogle Scholar
  • 60 Kokorine I, Marbaix E, Henriet P. et al . Focal cellular origin and regulation of interstitial collagenase (matrix metalloproteinase-1) are related to menstrual breakdown in the human endometrium.  J Cell Sci . 1996;  109( Pt 8) 2151-2160
    PubMedGoogle Scholar
  • 61 Salamonsen L A, Woolley D E. Matrix metalloproteinases in normal menstruation.  Hum Reprod . 1996;  11 (suppl 2) 124-133
    PubMedGoogle Scholar
  • 62 Marbaix E, Donnez J, Courtoy P J, Eeckhout Y. Progesterone regulates the activity of collagenase and related gelatinases A and B in human endometrial explants.  Proc Natl Acad Sci U S A . 1992;  89 11789-11793
    CrossrefPubMedGoogle Scholar
  • 63 Nayak N R, Critchley H O, Slayden O D. et al . 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 . 2000;  85 3442-3452
    CrossrefPubMedGoogle Scholar
  • 64 Zhang J, Hampton A L, Nie G, Salamonsen L A. Progesterone inhibits activation of latent matrix metalloproteinase (MMP)-2 by membrane-type 1 MMP: enzymes coordinately expressed in human endometrium.  Biol Reprod . 2000;  62 85-94
    PubMedGoogle Scholar
  • 65 Singer C F, Marbaix E, Lemoine P, Courtoy P J, Eeckhout Y. Local cytokines induce differential expression of matrix metalloproteinases but not their tissue inhibitors in human endometrial fibroblasts.  Eur J Biochem . 1999;  259 40-45
    CrossrefPubMedGoogle Scholar
  • 66 Keller N R, Sierra-Rivera E, Eisenberg E, Osteen K G. Progesterone exposure prevents matrix metalloproteinase-3 (MMP-3) stimulation by interleukin-1alpha in human endometrial stromal cells.  J Clin Endocrinol Metab . 2000;  85 1611-1619
    CrossrefPubMedGoogle Scholar
  • 67 Osteen K G, Bruner-Tran K L, Keller N R, Eisenberg E. Progesterone-mediated endometrial maturation limits matrix metalloproteinase (MMP) expression in an inflammatory-like environment: a regulatory system altered in endometriosis.  Ann NY Acad Sci . 2002;  955 37-406
    CrossrefPubMedGoogle Scholar
  • 68 Lockwood C J, Krikun G, Hausknecht V A, Papp C, Schatz F. Matrix metalloproteinase and matrix metalloproteinase inhibitor expression in endometrial stromal cells during progestin-initiated decidualization and menstruation-related progestin withdrawal.  Endocrinology . 1998;  139 4607-4613
    CrossrefPubMedGoogle Scholar
  • 69 Salamonsen L A, Woolley D E. Menstruation: induction by matrix metalloproteinases and inflammatory cells.  J Reprod Immunol . 1999;  44 1-27
    CrossrefPubMedGoogle Scholar
  • 70 Schatz F, Krikun G, Runic R. et al . Implications of decidualization-associated protease expression in implantation and menstruation.  Semin Reprod Endocrinol . 1999;  17 3-12
    PubMedGoogle Scholar
  • 71 Koks C A, Dunselman G A, de Goeij F A, Arends J W, Evers J L. Evaluation of a menstrual cup to collect shed endometrium for in vitro studies.  Fertil Steril . 1997;  68 560-564
    CrossrefPubMedGoogle Scholar
  • 72 Bruner-Tran K L, Webster-Clair D, Osteen K G. Experimental endometriosis: the nude mouse as a xenographic host.  Ann NY Acad Sci . 2002;  955 328-406
    PubMedGoogle Scholar
  • 73 Saito T, Mizumoto H, Kuroki K. et al . [Expression of MMP-3 and TIMP-1 in the endometriosis and the influence of danazol].  Nippon Sanka Fujinka Gakkai Zasshi . 1995;  47 495-496
    PubMedGoogle Scholar
  • 74 Sharpe-Timms K L, Keisler L W, McIntush E W, Keisler D H. Tissue inhibitor of metalloproteinase-1 concentrations are attenuated in peritoneal fluid and sera of women with endometriosis and restored in sera by gonadotropin-releasing hormone agonist therapy.  Fertil Steril . 1998;  69 1128-1134
    CrossrefPubMedGoogle Scholar
  • 75 Lessey B A, Metzger D A, Haney A F, McCarty Jr S K. Immunohistochemical analysis of estrogen and progesterone receptors in endometriosis: comparison with normal endometrium during the menstrual cycle and the effect of medical therapy.  Fertil Steril . 1989;  51 409-415
    PubMedGoogle Scholar
  • 76 Bergqvist A, Ferno M. Oestrogen and progesterone receptors in endometriotic tissue and endometrium: comparison of different cycle phases and ages.  Hum Reprod . 1993;  8 2211-2217
    PubMedGoogle Scholar
  • 77 Misao R, Iwagaki S, Fujimoto J, Sun W, Tamaya T. Dominant expression of progesterone receptor form B mRNA in ovarian endometriosis.  Horm Res . 1999;  52 30-34
    CrossrefPubMedGoogle Scholar
  • 78 Noble L S, Simpson E R, Johns A, Bulun S E. Aromatase expression in endometriosis.  J Clin Endocrinol Metab . 1996;  81 174-179
    CrossrefPubMedGoogle Scholar
  • 79 Zeitoun K, Takayama K, Sasano H. et al . Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.  J Clin Endocrinol Metab . 1998;  83 4474-4480
    CrossrefPubMedGoogle Scholar
  • 80 Tseng J F, Ryan I P, Milam T D. et al . Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis.  J Clin Endocrinol Metab . 1996;  81 1118-1122
    CrossrefPubMedGoogle Scholar
  • 81 Bruner K L, Keller N K, Osteen K G. Interleukin-1α opposes suppression of human endometrial matrix metalloproteinases by progesterone in a model of experimental endometriosis. In: Lemay A, Maheux R, eds. Understanding and Managing Endometriosis: Advances in Research and Practice New York: Parthenon 1998: 123-130
    Google Scholar
  • 82 Maas J W, Groothuis P G, Dunselman G A. et al . Development of endometriosis-like lesions after transplantation of human endometrial fragments onto the chick embryo chorioallantoic membrane.  Hum Reprod . 2001;  16 627-631
    CrossrefPubMedGoogle Scholar
  • 83 Wenzl R J, Heinzl H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants.  Gynecol Obstet Invest . 1998;  45 253-257
    CrossrefPubMedGoogle Scholar
  • 84 Chung H W, Wen Y, Chun S H. et al . Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness.  Fertil Steril . 2001;  75 152-159
    CrossrefPubMedGoogle Scholar
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