Complex Mechanisms of Matrix Metalloproteinases Involvement in Endometrial Physiology and Pathology—An Update

Matrix metalloproteinases (MMPs) belong to a multigenic family of proteolytic enzymes with great structural variability which provide a complex intervention in pathophysiological conditions. Our review is focused on both MMPs key role in physiological reproductive events, such as embryo implantation, uterine involution, normal endometrial cycle, and on their role in the main endometrial pathologies. MMPs activity is closely regulated by tissue inhibitors of MMPs (TIMPs). MMP: TIMP imbalance has been incriminated in various pathological conditions, including endometrial cancer and endometriosis. Accumulated data support the involvement of a large spectrum of MMPs and TIMPs in endometrial carcinogenesis. Strong MMP-2 and weak TIMP-2 tissue immunoexpressions have a powerful prognosis value, while MMP-9 high expression suggests its important involvement in endometrial tumor invasiveness. Endometriosis development implies an accumulation of events showing partial overlap with endometrial carcinogenesis and invasion, requiring MMPs involvement. Therefore, increased levels of several MMPs have been detected in peritoneal fluid and/or endometrial tissue of patients diagnosed with endometriosis. Endometriotic mesenchymal stem cells (MSCs) may be involved in the pathogenesis of endometriosis due to their upregulated expression for markers of migration and angiogenesis, such as MMP-2, MMP-3, MMP-9, and VEGF. The hypothesis of therapeutic benefits of synthetic MMPs inhibitors, added to the progesterone or progestins action, has been based on the complex MMPs involvement in endometrial pathology. Future research is necessary to elucidate the complex interactions between molecules involved in proliferation, angiogenesis and apoptosis, opening new perspectives in the early diagnosis and treatment of endometrial neoplasia and endometriosis. Access this chapter Tax calculation will be finalised at checkout Purchases are for personal use only Similar content being viewed by others

Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function and biochemistry. Circ Res 92:827–839 Ii M, Yamamoto H, Adachi Y et al (2006) Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med 231:20–27 Brummer O, Bohmer G, Hollwitz B et al (2002) MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation-an immunohistochemical study. Gynecol Oncol 84:222–227 Overall CM (2002) Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol Biotechnol 22:51–86 Johansson N, Ala-Aho R, Uitto V et al (2000) Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. J Cell Sci 113:227–235 Curry TE Jr, Osteen KG (2003) The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 24:428–465 Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C (2004) Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 48:411–424 Hashizume K (2007) Analysis of utero-placental-specific molecules and their functions during implantation and placentation in the bovine. J Reprod Dev 53:1–11 Osteen KG, Igarashi TM, Bruner-Tran KL (2003) Progesterone action in the human endometrium: induction of a unique tissue environment which limits matrix metalloproteinase (MMP) expression. Front Biosci 8:78–86 Yadav L, Puri N, Rastogi V et al (2014) Matrix metalloproteinases and cancer—roles in threat and therapy. Asian Pac J Cancer Prev 15:1085–1091 Shiomi T, Okada Y (2003) MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev 22:145–152 Amalinei C, Caruntu ID, Balan R (2007) Biology of metalloproteinases. Rom J Morphol Embryol 48:316–320 Wiseman BS, Sternlicht MD, Lund LR et al (2003) Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J Cell Biol 162:1123–1133 Bouloumie A, Sengenes C, Portolan G et al (2001) Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. Diabetes 50:2080–2086 Lambert V, Wielockx B, Munaut C et al (2003) MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J 17:2290–2292 Solberg H, Rinkenberger J, Danø K et al (2003) A functional overlap of plasminogen and MMPs regulates vascularization during placental development. Development 130:4439–4450 English JL, Kassiri Z, Koskivirta I et al (2006) Individual TIMP deficiencies differentially impact pro-MMP-2 activation. J Biol Chem 281:10337–10346 Lee MH, Murphy G (2004) Matrix metalloproteinases at a glance. J Cell Science 117:4015–4016 Mannello F, Gazzanelli G (2001) Tissue inhibitors of metalloproteinases and programmed cell death: Conundrums, controversies and potential implications. Apoptosis 6:479–482 Collette T, Bellehumeur C, Kats R et al (2004) Evidence for an increased release of proteolytic activity by the eutopic endometrial tissue in women with endometriosis and for involvement of matrix metalloproteinase-9. Hum Reprod 19:1257–1264 Seo DW, Li H, Guedez L et al (2003) TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114:171–180 Wang WM, Ge G, Lim NH et al (2006) TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. Biochem J 398:515–519 Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176 Qi JH, Ebrahem Q, Moore N et al (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9:407–415 Liu K, Wahlberg P, Hagglund AC, Ny T (2003) Expression pattern and functional studies of matrix degrading proteases and their inhibitors in the mouse corpus luteum. Mol Cell Endocrinol 31:131–140 Oh J, Seo DW, Diaz T et al (2004) Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Res 64:9062–9069 Baker AH, Edwards DR, Murphy G (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115:3719–3727 Jiang Y, Goldberg ID, Shi YE (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 28:2245–2252 Velasco G, Pendás AM, Fueyo A et al (1999) Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem 274:4570–4576 Freitas S, Meduri G, Le Nestour E et al (1999) Expression of metalloproteinases and their inhibitors in blood vessels in human endometrium. Biol Reprod 61:1070–1082 D’Ippolito S, Marana R, Di Nicuolo F et al (2012) Effect of low molecular weight heparins (LMWHs) on antiphospholipid antibodies (aPL)-mediated inhibition of endometrial angiogenesis. PLoS ONE 7(1):e29660. doi:10.1371/journal.pone.0029660 Lockwood CJ (2011) Mechanisms of normal and abnormal endometrial bleeding. Menopause 18:408–411 Cornet PB, Galant C, Eeckhout Y et al (2005) Regulation of matrix metalloproteinase-9/gelatinase B expression and activation by ovarian steroids and LEFTY-A/endometrial bleeding-associated factor in the human endometrium. J Clin Endocrinol Metab 90:1001–1011 Nissi R, Talvensaari-Mattila A, Kotila V et al (2013) Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy failure. Reprod Biol Endocrinol 11:2. doi:10.1186/1477-7827-11-2 Moindjie H, Santos ED, Loeuillet L et al (2014) Preimplantation factor (PIF) promotes human trophoblast invasion. Biol Reprod 91:118. doi:10.1095/biolreprod.114.119156 Zhuang Y, Qian Z, Huang L (2014) Elevated expression levels of matrix metalloproteinase-9 in placental villi and tissue inhibitor of metalloproteinase-2 in decidua are associated with prolonged bleeding after mifepristone-misoprostol medical abortion. Fertil Steril 101:166–171 Lockwood CJ, Basar M, Kayisli UA et al (2014) Interferon-γ protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia. Am J Pathol 184:2549–2559 Ishikawa T, Harada T, Kubota T, Aso T (2007) Testosterone inhibits matrix metalloproteinase-1 production in human endometrial stromal cells in vitro. Reproduction 133:1233–1239 Graesslin O, Cortez A, Fauvet M et al (2006) Metalloproteinase-2, -7 and -9 and tissue inhibitor of metalloproteinase-1 and -2 expression in normal, hyperplastic and neoplastic endometrium: a clinical-pathological correlation study. Ann Oncol 17:637–645 Galant C, Berliere M, Dubois D et al (2004) Focal expression and final activity of matrix metalloproteinases may explain irregular dysfunctional endometrial bleeding. Am J Pathol 165:83–94 Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573 Yi YC, Chou PT, Chen LY et al (2010) Matrix metalloproteinase-7 (MMP-7) polymorphism is a risk factor for endometrial cancer susceptibility. Clin Chem Lab Med 48:337–344 Ueno H, Yamashita K, Azumano I et al (1999) Enhanced production and activation of matrix metalloproteinase-7 (matrilysin) in human endometrial carcinomas. Int J Cancer 84:470–477 Määtä M, Soini Y, Liakka A, Autio-Harmainen H (2000) Localisation of MT1-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 114:402–411 Hojilla CV, Mohammed FF, Khokha R (2003) Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. Br J Cancer 10:1817–1821 Amalinei C, Caruntu ID, Balan R et al (2008) Contribution of immunohistochemistry and flow-cytometry in the study of endometrial pathology. Rev Med Chir Soc Med Nat Iasi 112:437–448 Amalinei C, Caruntu ID, Giusca SE, Balan RA (2010) Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol 51:215–228 Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174 Amalinei C, Cianga C, Balan R et al (2011) Immunohistochemical analysis of steroid receptors, proliferation markers, apoptosis related molecules, and gelatinases in non-neoplastic and neoplastic endometrium. Ann Anat 193:43–55 Park DW, Ryu HS, Choi DS et al (2001) Localization of matrix metalloproteinases on endometrial cancer cell invasion in vitro. Gynecol Oncol 82:442–449 Honkavuori M, Talvensaari-Mattila A, Soini Y et al (2007) MMP-2 expression associates with CA 125 and clinical course in endometrial carcinoma. Gynecol Oncol 104:217–221 McLaughlin B, Weiss JB (1996) Endothelial-cell-stimulating angiogenesis factor (ESAF) activates progelatinase A (72 kDa type IV collagenase), prostromelysin 1 and procollagenase and reactivates their complexes with tissue inhibitors of metalloproteinases: a role for ESAF in non-inflammatory angiogenesis. Biochem J 317:739–745 Aglund K, Rauvala M, Puistola U et al (2004) Gelatinases A and B (MMP-2 and MMP-9) in endometrial cancer—MMP-9 correlates to the grade and the stage. Gynecol Oncol 94:699–704 Honkavuori-Toivola M, Talvensaari-Mattila A, Soini Y et al (2012) Immunoreactivity for TIMP-2 is associated with a favorable prognosis in endometrial carcinoma. Tumor Biol 33:935–941 Honkavuori-Toivola M, Santala M, Soini Y et al (2013) Combination of strong MMP-2 and weak TIMP-2 immunostainings is a significant prognostic factor in endometrial carcinoma. Dis Markers 35:261–266 Talvensaari-Mattila A, Santala M, Soini Y, Turpeenniemi-Hujanen T (2005) Prognostic value of matrix metalloproteinase-2 (MMP-2) expression in endometrial endometrioid adenocarcinoma. Anticancer Res 25:4101–4105 Laas E, Ballester M, Cortez A et al (2014) Supervised clustering of immunohistochemical markers to distinguish atypical endometrial hyperplasia from grade 1 endometrial cancer. Gynecol Oncol 133:205–210 Grybos A, Bar J (2014) The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer. Folia Histochem Cytobiol 52:187–194 Jedryka M, Chrobak A, Chelmonska-Soyta A et al (2012) Matrix metalloproteinase (MMP)-2 and MMP-9 expression in tumor infiltrating CD3 lymphocytes from women with endometrial cancer. Int J Gynecol Cancer 22:1303–1309 Srdelić Mihalj S, Kuzmić-Prusac I, Zekić-Tomaš S et al (2014) Lipocalin-2 and matrix metalloproteinase-9 expression in high-grade endometrial cancer and their prognostic value. Histopathology 17. doi:10.1111/his.12633 Mannelqvist M, Stefansson IM, Wik E et al (2012) Lipocalin 2 expression is associated with aggressive features of endometrial cancer. BMC Cancer 12:169 Nishi H, Kuroda M, Isaka K (2013) Estrogen and estrogen receptor induce matrix metalloproteinase-26 expression in endometrial carcinoma cells. Oncol Rep 30:751–756 Nabeshima K, Iwasaki H, Nishio J et al (2006) Expression of emmprin and matrix metalloproteinases (MMPs) in peripheral nerve sheath tumors: emmprin and membrane-type (MT)1-MMP expressions are associated with malignant potential. Anticancer Res 26:1359–1367 Yan L, Zucker S, Toole BP (2005) Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumour progression. Thromb Haemost 93:199–204 Muramatsu T, Miyauchi T (2003) Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion. Histol Histopathol 18:981–987 Tang Y, Nakada MT, Kesavan P et al (2005) Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res 65:3193–3199 Ueda K, Yamada K, Urashima M et al (2007) Association of extracellular matrix metalloproteinase inducer in endometrial carcinoma with patient outcomes and clinicopathogenesis using monoclonal antibody 12C3. Oncol Rep 17:731–735 Nakamura K, Kodama J, Hogo A, Hiramatsu Y (2012) Role of emmprin in endometrial cancer. BMC Cancer 12:191–201 Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829 Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939 Khoufache K, Bazin S, Girard K et al (2012) Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo. PLoS ONE 7:e37264 Londero AP, Calcagno A, Grassi T et al (2012) Survivin, MMP-2, MT1-MMP, and TIMP-2: their impact on survival, implantation, and proliferation of endometriotic tissues. Virchows Arch 461:589–599 Suzumori N, Ozaki Y, Ogasawara M, Suzumori K (2001) Increased concentrations of cathepsin D in peritoneal fluid from women with endometriosis. Mol Hum Reprod 7:459–462 Mizumoto H, Saito T, Ashihara K et al (2002) Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay. Life Sci 71:259–273 Scotti S, Regidor PA, Schindler AE, Winterhager E (2000) Reduced proliferation and cell adhesion in endometriosis. Mol Hum Reprod 6:610–617 Chen GT, Tai CT, Yeh LS et al (2002) Identification of the cadherin subtypes present in the human peritoneum and endometriotic lesions: potential role for P-cadherin in the development of endometriosis. Mol Reprod Dev 62:289–294 Ueda M, Yamashita Y, Takehara M et al (2002) Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis. Gynecol Endocrinol 16:391–402 Moreno-Bueno G, Gamallo C, Pérez-Gallego L et al (2001) beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol 10:116–122 Jana SK, Banerjee P, Mukherjee R et al (2013) HOXA-11 mediated dysregulation of matrix remodeling during implantation window in women with endometriosis. J Assist Reprod Genet 30:1505–1512 Malvezzi H, Aguiar VG, Paz CC et al (2013) Increased circulating MMP-2 levels in infertile patients with moderate and severe pelvic endometriosis. Reprod Sci 20:557–562 Antsiferova Y, Sotnikova N (2012) The local immune mechanisms involved in the formation of endometriotic lesions. In: Chaudhury K, Chakravarty B (eds) Endometriosis—basic concepts and current research trends. ISBN 978-953-51-0524-4, 11: 211-244. doi:10.5772/29965 Yeaman GR, Collins JE, Lang GA (2002) Autoantibody responses to carbohydrate epitopes in endometriosis. Ann N Y Acad Sci 955:174–182 Cominelli A, Gaide Chevronnay HP, Lemoine P et al (2014) Matrix metalloproteinase-27 is expressed in CD163+/CD206+ M2 macrophages in the cycling human endometrium and in superficial endometriotic lesions. Mol Hum Reprod 20:767–775 Trovó de Marqui AB (2012) Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling. Rev Assoc Med Bras 58:620–632 Iarmolinskaia MI, Molotkov AS, Bezhenar VF et al (2014) Association of matrix metalloproteinases’ polymorphisms of MMP3 and MMP9 with development of genital endometriosis. Genetika 50:230–235 Yuan C, Zhang L, Gao Y et al (2014) DNA demethylation at the promoter region enhances the expression of MMP-9 in ectopic endometrial stromal cells of endometriosis. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 30:1258–1261 Koippallil Gopalakrishnan Nair AR, Pandit H, Warty N, Madan T (2015) Endometriotic mesenchymal stem cells exhibit a distinct immune phenotype. Int Immunol 27:195–204 Fierro IM, Colgan SP, Bernasconi G et al (2003) Lipoxin A4 and aspirin-triggered 15-epi-LipoxinA4 inhibit human neutrophil nigration: comparisons between synthetic 15 epimers in chemotaxis and transmigration with microvessel endothelial cells and epithelial cells. J Immunol 170:2688–2694 Kumar R, Clerc AC, Gori I et al (2014) Lipoxin A4 prevents the progression of de novo and established endometriosis in a mouse model by attenuating prostaglandin E2 production and estrogen signaling. PLoS ONE 24:e89742 Wu R, Zhou W, Chen S et al (2014) Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol 171:4927–4940 Bayoglu Tekin Y, Guven S, Kirbas A et al (2015) Is resveratrol a potential substitute for leuprolide acetate in experimental endometriosis? Eur J Obstet Gynecol Reprod Biol 184:1–6 Tamaki K, Tanzawa K, Kurihara S et al (1995) Synthesis and structure-activity relationships of gelatinase inhibitors derived from matlystatins. Chem Pharm Bull 43:1883–1893 Conway JG, Trexler SJ, Wakefield JA et al (1996) Effect of matrix metalloproteinase inhibitors on tumor growth and spontaneous metastatsis. Clin Exp Metastasis 14:115–124 Brown PD (1998) Matrix metalloproteinase inhibitors. Angiogenesis 1:142–154 Bottomley KM Borkakoti N, Bradshaw D et al (1997) Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors. Biochem J 323:483–488 Rigot V, Marbaix E, Lemoine P et al (2001) In vivo perimenstrual activation of progelatinase B (proMMP-9) in the human endometrium and its dependence on stromelysin 1 (MMP-3) ex vivo. Biochem J 358:275–280 Salamonsen LA, Butt AR, Hammond FR et al (1997) 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 82:1409–1415 Prifti S, Lelle I, Zhong G et al (2004) Matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression is not regulated by norgestimate or norelgestromin. Gynecol Endocrinol 18:23–27 Hampton AL, Nie G, Salamonsen LA (1999) Progesterone analogues similarly modulate endometrial matrix metalloproteinase-1 and matrixmetalloproteinase-3 and their inhibitor in a model for long-term contraceptive effects. Mol Hum Reprod 5:365–371 Rawdanowicz TJ, Hampton AL, Nagase H et al (1994) 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 79:530–536 Singer CF, Marbaix E, Lemoine P et al (1999) Local cytokines induce differential expression of matrix metalloproteinases but not their tissue inhibitors in human endometrial fibroblasts. Eur J Biochem 259:40–45 Bruner KL, Rodgers WH, Gold LI et al (1995) Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci USA 92:7362–7366 Zhang Y, McCluskey K, Fujii K, Wahl LM (1998) Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin-dependent and -independent mechanisms. J Immunol 161:3071–3076 Lau TM, Witjaksono J, Affandi B, Rogers PA (1996) Expression of progesterone receptor mRNA in the endometrium during the normal menstrual cycle and in Norplant users. Hum Reprod 11:2629–2634 Mertens HJ, Heineman MJ, Koudstaal J et al (1996) Androgen receptor content in human endometrium. Eur J Obstet Gynecol Reprod Biol 70:11–13 Wilson CM, McPhaul MJ (1996) A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol 120:51–57 Schneikert J, Peterziel H, Defossez PA et al (1996) Androgen receptor-Ets protein interaction is a novel mechanism for steroid hormone-mediated down-modulation of matrix metalloproteinase expression. J Biol Chem 271:23907–23913 Author information Authors and Affiliations Corresponding author Editor information Editors and Affiliations Rights and permissions Copyright information © 2017 Springer Nature Singapore Pte Ltd. About this chapter Cite this chapter Amalinei, C., Căruntu, ID., Giuşcă, S.E., Balan, R.A. (2017). Complex Mechanisms of Matrix Metalloproteinases Involvement in Endometrial Physiology and Pathology—An Update. In: Chakraborti, S., Chakraborti, T., Dhalla, N. (eds) Proteases in Human Diseases. 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