Matrix-Metalloproteinasen (MMPs) und deren Bedeutung für die Menstruation und Endometriose

Zusammenfassung

Die Endometriose ist neben der Ausbildung von Myomen die häufigste benigne proliferative Erkrankung der Frau im reproduktionsfähigen Alter. Obwohl die Entstehung als auch das weitere Wachstum von Endometrioseherden durch ovarielle Steroide wesentlich beeinflusst wird, ist die genauere Pathogenese dieser Erkrankung nach wie vor ungeklärt. Da der bereits vor 70 Jahren postulierte Mechanismus der retrograden Menstruation auch bei einer Vielzahl von gesunden Patientinnen beobachtet werden kann, dürfte die Implantations- und Invasionsfähigkeit von ektopen Endometriumzellen entscheidend für die Entstehung der Endometriose sein. In diesem Zusammenhang zeigen morphologische, immunologische und biochemische Untersuchungen eine direkte Korrelation zwischen Vorhandensein und Wachstum von Endometriose und der Expression von extrazellulärer-Matrix auflösenden Enzymen, so genannten Matrix-Metalloproteinasen, welche auch im Rahmen der Menstruation wesentlich an der Abstoßung des Stratum functionale beteiligt sind. Die Aktivität von MMPs wird hauptsächlich durch ovarielle Steroide und die lokale Sekretion von Zytokinen reguliert. Das Verständnis und die weitere Erforschung dieser und anderer assoziierter Substanzklassen kann weiter zur Klärung der Pathogenese der Endometriose beitragen und auf mögliche medikamentöse Therapieansätze hinweisen.

Abstract

Endometriosis is one of the most common benign proliferative disorders of the female genital tract and occurs in up to 20 % of women, leading to symptoms such as chronic pelvic pain, dyspareunia, dysmenorrhea but also sterility. Although retrograde menstruation represents a plausible explanation for the development of endometriosis, several additional factors have to contribute to the establishment, invasion and growth of endometriotic lesions since endometrial cells spilled into the peritoneal cavity can also be detected in the majority of women without evidence of disease. Within this, the ability of endometrial tissue to implant and invade the peritoneal surfaces and underlying tissues appears to be a pathogenic key mechanism for the growth of endometrium outside the uterine cavity. Matrix metalloproteinases (MMPs) constitute a group of enzymes that not only mediate physiologic tissue turnover such as endometrial breakdown at menstruation, but also have been shown to play important roles in the development of invasive and destructive diseases. The altered regulation of endometrial MMPs has therefore also been associated with the pathogenesis of endometriosis, linking the invasive potential of refluxed endometrium to the adhaesion and growth of endometriotic cells. The aim of present work is to review the role of MMPs in processes of menstruation and development of endometriosis.

Schlüsselwörter

Endometriose - Gewebsauflösung - MMP - Zytokine - Wachstum

Key words

endometriosis - menstruation - tissue degradation - MMPs

Literatur

• 1 Brosens I A, Brosens J J. Endometriosis.  Eur J Obstet Gynecol Reprod Biol. 2000;  90 159-164
• 2 Goldman M B, Cramer D W. The epidemiology of endometriosis.  Prog Clin Biol Res. 1990;  323 15-31
• 3 Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium.  Hum Reprod. 2002;  17 2725-2736
• 4 Halme J, Hammond M G, Hulka J F, Raj S G, Talbert L M. Retrograde menstruation in healthy women and in patients with endometriosis.  Obstet Gynecol. 1984;  64 151-154
• 5 Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. Endometriosis: the pathophysiology as an estrogen-dependent disease.  J Steroid Biochem Mol Biol. 2002;  83 149-155
• 6 Salamonsen L A, Woolley D E. Matrix metalloproteinases in normal menstruation.  Hum Reprod. 1996;  11 (Suppl 2) 124-133
• 7 Henriet P, Cornet P B, Lemoine P, Galant C, Singer C F, Courtoy P J, Eeckhout Y, Marbaix E. Circulating ovarian steroids and endometrial matrix metalloproteinases (MMPs).  Ann NY Acad Sci. 2002;  955 119-138
• 8 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
• 9 Hulboy D L, Rudolph L A, Matrisian L M. Matrix metalloproteinases as mediators of reproductive function.  Mol Hum Reprod. 1997;  3 27-45
• 10 Singer C F, Kronsteiner N, Marton E, Kubista M, Cullen K J, Hirtenlehner K, Seifert M, Kubista E. MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions.  Breast Cancer Res Treat. 2002;  72 69-77
• 11 Singer C F, Rasmussen A, Lippman M E, Cullen K J. Coexpression of stromelysin-3 and insulin-like growth factor II in tumors of ectodermal, mesodermal, and endodermal origin: indicator of a fetal cell phenotype.  J Clin Endocrinol Metab. 1997;  82 1917-1922
• 12 Curry Jr T E, Osteen K G. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus.  Biol Reprod. 2001;  64 1285-1296
• 13 Singer C F, Marbaix E, Kokorine I, Lemoine P, Donnez J, Eeckhout Y, Courtoy P J. Paracrine stimulation of interstitial collagenase (MMP-1) in the human endometrium by interleukin 1alpha and its dual block by ovarian steroids.  Proc Natl Acad Sci USA. 1997;  94 10341-10345
• 14 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 37-47
• 15 Osteen K G, Yeaman G R, Bruner-Tran K L. Matrix metalloproteinases and endometriosis.  Semin Reprod Med. 2003;  21 155-164
• 16 Freitas S, Meduri G, Le Nestour E, Bausero P, Perrot-Applanat M. Expression of metalloproteinases and their inhibitors in blood vessels in human endometrium.  Biol Reprod. 1999;  61 1070-1082
• 17 Sillem M, Prifti S, Koch A, Neher M, Jauckus J, Runnebaum B. Regulation of matrix metalloproteinases and their inhibitors in uterine endometrial cells of patients with and without endometriosis.  Eur J Obstet Gynecol Reprod Biol. 2001;  95 167-174
• 18 Chung H W, Wen Y, Chun S H, Nezhat C, Woo B H, Lake Polan M. 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
• 19 Chung H W, Lee J Y, Moon H S, Hur S E, Park M H, Wen Y, Polan M L. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium.  Fertil Steril. 2002;  78 787-795
• 20 Ria R, Loverro G, Vacca A, Ribatti D, Cormio G, Roccaro A M, Selvaggi L. Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas.  Eur J Clin Invest. 2002;  32 199-206
• 21 Wenzl R J, Heinzl H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants.  Gynecol Obstet Invest. 1998;  45 253-257
• 22 Hudelist G, Lass H, Keckstein J, Walter I, Wieser F, Wenzl R, Mueller R, Czerwenka K, Kubista E, Singer C F. Interleukin 1alpha and tissue-lytic matrix metalloproteinase-1 are elevated in ectopic endometrium of patients with endometriosis.  Hum Reprod. 2005;  20 1695-1701
• 23 Kokorine I, Nisolle M, Donnez J, Eeckhout Y, Courtoy P J, Marbaix E. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions.  Fertil Steril. 1997;  68 246-251
• 24 Bruner-Tran K L, Eisenberg E, Yeaman G R, Anderson T A, McBean J, Osteen K G. 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
• 25 Ueda M, Yamashita Y, Takehara M, Terai Y, Kumagai K, Ueki K, Kanda K, Hung Y C, Ueki M. Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis.  Gynecol Endocrinol. 2002;  16 391-402
• 26 Hudelist G, Keckstein J, Czerwenka K, Lass H, Walter I, Auer M, Wieser F, Wenzl R, Kubista E, Singer C F. Estrogen receptor beta and Matrix-Metalloproteinase 1 (MMP-1) are coexpressed in uterine endometrium and endometriotic lesions of patients with endometriosis.  Fertil Steril. 2005;  in press
• 27 Lessey B A, Metzger D A, Haney A F, McCarty Jr K S. 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
• 28 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
• 29 Noble L S, Simpson E R, Johns A, Bulun S E. Aromatase expression in endometriosis.  J Clin Endocrinol Metab. 1996;  81 174-179
• 30 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
• 31 Kao L C, Germeyer A, Tulac S, Lobo S, Yang J P, Taylor R N, Osteen K, Lessey B A, Giudice L C. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility.  Endocrinology. 2003;  144 2870-2881
• 32 Kao L C, Tulac S, Lobo S, Imani B, Yang J P, Germeyer A, Osteen K, Taylor R N, Lessey B A, Giudice L C. Global gene profiling in human endometrium during the window of implantation.  Endocrinology. 2002;  143 2119-2138
• 33 Rawdanowicz T J, Hampton A L, Nagase H, Woolley D E, Salamonsen L A. Matrix metalloproteinase production by cultured human endometrial stromal cells: identification of interstitial collagenase, gelatinase-A, gelatinase-B, and stromelysin-1 and their differential regulation by interleukin-1 alpha and tumor necrosis factor-alpha.  J Clin Endocrinol Metab. 1994;  79 530-536
• 34 Wolber E M, Kressin P, Meyhofer-Malik A, Diedrich K, Malik E. Differential induction of matrix metalloproteinase 1 and 2 in ectopic endometrium.  Reprod Biomed Online. 2003;  6 238-243
• 35 Akoum A, Lawson C, McColl S, Villeneuve M. Ectopic endometrial cells express high concentrations of interleukin (IL)-8 in vivo regardless of the menstrual cycle phase and respond to oestradiol by up-regulating IL-1-induced IL-8 expression in vitro.  Mol Hum Reprod. 2001;  7 859-866
• 36 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
• 37 Schweppe K W. [The ranking of the gestagens in the treatment of pain caused by endometriosis - an overview].  Zentralbl Gynakol. 2003;  125 276-280
• 38 Bartley J, Mechsner S, Beutler C, Halis G, Lange J, Ebert A D. [COX-2-expression in extragenital endometriosis lesions as a novel therapeutical approach?].  Zentralbl Gynakol. 2003;  125 252-255
• 39 Matsuzaki S, Canis M, Pouly J L, Wattiez A, Okamura K, Mage G. Cyclooxygenase-2 expression in deep endometriosis and matched eutopic endometrium.  Fertil Steril. 2004;  82 1309-1315
• 40 Matsuzaki S, Canis M, Darcha C, Dallel R, Okamura K, Mage G. Cyclooxygenase-2 selective inhibitor prevents implantation of eutopic endometrium to ectopic sites in rats.  Fertil Steril. 2004;  82 1609-1615