Skip to main content

Advertisement

SpringerLink
Log in

EMMPRIN Is Secreted by Human Uterine Epithelial Cells in Microvesicles and Stimulates Metalloproteinase Production by Human Uterine Fibroblast Cells

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

An Erratum to this article was published on 01 January 2015

This article has been updated

Abstract

Endometrial remodeling is a physiological process involved in the gynecological disease, endometriosis. Tissue remodeling is directed by uterine fibroblast production of matrix metalloproteinases (MMPs). Several MMPs are regulated directly by the protein extracellular matrix metalloproteinase inducer (EMMPRIN) and also by proinflammatory cytokines such as interleukin (IL)1-α/β. We hypothesized that human uterine epithelial cells (HESs) secrete intact EMMPRIN to stimulate MMPs. Microvesicles from HES cell-conditioned medium (CM) expressed intact EMMPRIN protein. Treatment of HES cells with estradiol or phorbyl 12-myristate-13-acetate increased the release of EMMPRIN-containing microvesicles. The HES CM stimulated MMP-1, -2, and -3 messenger RNA levels in human uterine fibroblasts (HUFs) and EMMPRIN immunodepletion from HES-cell concentrated CM reduced MMP stimulation (P < .05). Treatment of HUF cells with low concentrations of IL-1β/α stimulated MMP production (P < .05). These results indicate that HES cells regulate MMP production by HUF cells by secretion of EMMPRIN, in response to ovarian hormones, proinflammatory cytokines as well as activation of protein kinase C.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Change history

  • 30 December 2015

    Braundmeier AG, Dayger CA, Mehrotra P, Belton RJ Jr, Nowak RA. EMMPRIN is secreted by human uterine epithelial cells in microvesicles and stimulates metalloproteinase production by human uterine fibroblast cells. Reprod Sci. 2012;19(12):1292–1301 (Original doi:10.1177/1933719112450332).

References

  1. Curry TE JrOsteen KG. The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev. 2003;24(4):428–465.

    Article  CAS  PubMed  Google Scholar 

  2. Chou CS, Tai CJ, MacCalman CD, Leung PC. Dose-dependent effects of gonadotropin releasing hormone on matrix metalloproteinase (MMP)-2, and MMP-9 and tissue specific inhibitor of metalloproteinases-1 messenger ribonucleic acid levels in human decidual stromal cells in vitro. J Clin Endocrinol Metab. 2003; 88(2):680–688.

    Article  CAS  PubMed  Google Scholar 

  3. Dong JC, Dong H, Campana A, Bischof P. Matrix metalloproteinases and their specific tissue inhibitors in menstruation. Reproduction. 2002;123(5):621–631.

    Article  CAS  PubMed  Google Scholar 

  4. Bruner-Tran KL, Eisenberg E, Yeaman GR, Anderson TA, McBean J, Osteen KG. 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(10):4782–4791.

    Article  CAS  PubMed  Google Scholar 

  5. Chen L, Nakai M, Belton RJ JrNowak RA. Expression of extracellular matrix metalloproteinase inducer and matrix metalloproteinases during mouse embryonic development. Reproduction. 2007;133(2):405–414.

    Article  CAS  PubMed  Google Scholar 

  6. Chen L, Belton RJ JrNowak RA. Basigin-mediated gene expression changes in mouse uterine stromal cells during implantation. Endocrinology. 2009;150(2):966–976.

    Article  CAS  PubMed  Google Scholar 

  7. Strakova Z, Szmidt M, Srisuparp S, Fazleabas AT. Inhibition of matrix metalloproteinases prevents the synthesis of insulin-like growth factor binding protein-1 during decidualization in the baboon. Endocrinology. 2003;144(12):5339–5346.

    Article  CAS  PubMed  Google Scholar 

  8. Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007;14(4):241–260.

    Article  PubMed  Google Scholar 

  9. Sampson J. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the pelvic cavity. Am J Obstet Gynecol. 1927;14:422–469.

    Article  Google Scholar 

  10. D’Hooghe TM, Nugent NP, Cuneo S, et al. Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drugcontrolled study. Biol Reprod. 2006;74(1):131–136.

    Article  PubMed  CAS  Google Scholar 

  11. Kyama CM, Mihalyi A, Simsa P, et al. Role of cytokines in the endometrial-peritoneal cross-talk and development of endometriosis. Front Biosci (Elite Ed). 2009;1:444–454.

    Article  Google Scholar 

  12. Sotnikova NY, Antsiferova YS, Posiseeva LV, Shishkov DN, Posiseev DV, Filippova ES. Mechanisms regulating invasiveness and growth of endometriosis lesions in rat experimental model and in humans. Fertil Steril. 15 2010;93(8):2701–2705.

    Article  PubMed  Google Scholar 

  13. Podgaec S, Dias Junior JA, Chapron C, Oliveira RM, Baracat EC, Abrao MS. Th1 and Th2 ummune responses related to pelvic endometriosis. Rev Assoc Med Bras. 2011;56(1):92–98.

    Article  Google Scholar 

  14. Osteen KG, Igarashi TM, Yeaman GR, Bruner-Tran KL. Steroid and cytokine regulation of matrix metalloproteinases and the pathophysiology of endometriosis. Gynecol Obstet Invest. 2004; 57(1):53–54.

    CAS  PubMed  Google Scholar 

  15. Braundmeier AG, Nowak RA. Cytokines regulate matrix metalloproteinases in human uterine endometrial fibroblast cells through a mechanism that does not involve increases in extracellular matrix metalloproteinase inducer. Am J Reprod Immunol. 2006; 56(3):201–214.

    Article  CAS  PubMed  Google Scholar 

  16. Di Carlo C, Bonifacio M, Tommaselli GA, Bifulco G, Guerra G, Nappi C. Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium. Fertil Steril. 2009;91(6):2315–2323.

    Article  PubMed  CAS  Google Scholar 

  17. Osteen KG, Yeaman GR, Bruner-Tran KL. Matrix metalloproteinases and endometriosis. Semin Reprod Med. 2003;21(2): 155–164.

    Article  CAS  PubMed  Google Scholar 

  18. 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(2):167–174.

    Article  CAS  PubMed  Google Scholar 

  19. Monckedieck V, Sannecke C, Husen B, et al. Progestins inhibit expression of MMPs and of angiogenic factors in human ectopic endometrial lesions in a mouse model. Mol Hum Reprod. 2009; 15(10):633–643.

    Article  PubMed  CAS  Google Scholar 

  20. Zhou WD, Yang HM, Wang Q, et al. SB203580, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis by down-regulating proinflammatory cytokines and proteolytic factors in a mouse model. Hum Reprod. 2010; 25(12):3110–3116.

    Article  CAS  PubMed  Google Scholar 

  21. Sillem M, Hahn U, Coddington CC 3rdGordon K, Runnebaum B, Hodgen GD. Ectopic growth of endometrium depends on its structural integrity and proteolytic activity in the cynomolgus monkey (Macaca fascicularis) model of endometriosis. Fertil Steril. 1996;66(3):468–473.

    Article  CAS  PubMed  Google Scholar 

  22. Braundmeier AG, Fazleabas AT, Lessey BA, Guo H, Toole BP, Nowak RA. Extracellular matrix metalloproteinase inducer regulates metalloproteinases in human uterine endometrium. J Clin Endocrinol Metab. 2006;91(6):2358–2365.

    Article  CAS  PubMed  Google Scholar 

  23. Noguchi Y, Sato T, Hirata M, Hara T, Ohama K, Ito A. Identification and characterization of extracellular matrix metalloproteinase inducer in human endometrium during the menstrual cycle in vivo and in vitro. J Clin Endocrinol Metab. 2003;88(12): 6063–6072.

    Article  CAS  PubMed  Google Scholar 

  24. Belton RJ JrChen L, Mesquita FS, Nowak RA. Basigin-2 is a cell surface receptor for soluble basigin ligand. J Biol Chem. 2008; 283(26):17805–17814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sidhu SS, Mengistab AT, Tauscher AN, LaVail J, Basbaum C. The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene. 2004;23(4):956–963.

    Article  CAS  PubMed  Google Scholar 

  26. Tang Y, Kesavan P, Nakada MT, Yan L. Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN. Mol Cancer Res. 2004;2(2):73–80.

    CAS  PubMed  Google Scholar 

  27. Strakova Z, Srisuparp S, Fazleabas AT. Interleukin-1beta induces the expression of insulin-like growth factor binding protein-1 during decidualization in the primate. Endocrinology. 2000;141(12): 4664–4670.

    Article  CAS  PubMed  Google Scholar 

  28. Richards RG, Brar AK, Frank GR, Hartman SM, Jikihara H. Fibroblast cells from term human decidua closely resemble endometrial stromal cells: induction of prolactin and insulin-like growth factor binding protein-1 expression. Biol Reprod. 1995; 52(3):609–615.

    Article  CAS  PubMed  Google Scholar 

  29. Kessler CA, Moghadam KK, Schroeder JK, Buckley AR, Brar AK, Handwerger S. Cannaboid receptor I activation markedly inhibits human decidualization. Mol Cell Endocrinol. 2005; 229(1–2):65–74.

    Article  CAS  PubMed  Google Scholar 

  30. Banerjee P, Sapru K, Strakova Z, Fazleabas AT. Chorionic gonadotropin regulates prostaglandin E synthase via a phosphatidylinositol 3-kinase-extracellular regulatory kinase pathway in a human endometrial epithelial cell line: implications for endometrial responses for embryo implantation. Endocrinology. 2009; 150(9):4326–4337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Desai NN, Kennard EA, Kniss DA, Friedman CI. Novel human endometrial cell line promotes blastocyst development. Fertil Steril. 1994;61(4):760–766.

    Article  CAS  PubMed  Google Scholar 

  32. Atay S, Gercel-Taylor C, Kesimer M, Taylor DD. Morphologic and proteomic characterization of exosomes released by cultured extravillous trophoblast cells. Exp Cell Res. 2011;317(8): 1192–1202.

    Article  CAS  PubMed  Google Scholar 

  33. Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 2009;19(2):43–51.

    Article  CAS  PubMed  Google Scholar 

  34. Dziunycz P, Milewski L, Radomski D, et al. Elevated ghrelin levels in the peritoneal fluid of patients with endometriosis: associations with vascular endothelial growth factor (VEGF) and inflammatory cytokines. Fertil Steril. 2009;92(6): 1844–1849.

    Article  CAS  PubMed  Google Scholar 

  35. Agrawal SM, Yong VW. The many faces of EMMPRIN—roles in neuroinflammation. Biochim Biophys Acta. 2011;1812(2): 213–219.

    Article  CAS  PubMed  Google Scholar 

  36. Ruiz S, Castro-Castro A, Bustelo XR. CD147 inhibits the nuclear factor of activated T-cells by impairing Vav1 and Rac1 downstream signaling. J Biol Chem. 2008;283(9):5554–5566.

    Article  CAS  PubMed  Google Scholar 

  37. Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M. Cyclophilin-CD147 interactions: a new target for antiinflammatory therapeutics. Clin Exp Immunol. 2010;160(3): 305–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Southcombe J, Tannetta D, Redman C, Sargent I. The immunomodulatory role of syncytiotrophoblast microvesicles. PLoS One. 2011;6(5):e20245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang Y, Hua Z, Zhang K, Meng K, Hu Y. Therapeutic effects of anticoagulant agents on preeclampsia in a murine model induced by phosphatidylserine/phosphatidylcholine microvesicles. Placenta. 2009;30(12): 1065–1070.

    Article  CAS  PubMed  Google Scholar 

  40. Gardiner C, Tannetta DS, Simms CA, Harrison P, Redman CW, Sargent IL. Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity. PLoS One. 2011;6(10):e26313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, et al. Tumourderived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother. 2006;55(7): 808–818.

    Article  CAS  PubMed  Google Scholar 

  42. Taylor PM, Woodfield RJ, Hodgkin MN, et al. Breast cancer cellderived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway. Oncogene. 2002;21(37):5765–5772.

    Article  CAS  PubMed  Google Scholar 

  43. Chavez-Munoz C, Morse J, Kilani R, Ghahary A. Primary human keratinocytes externalize stratifin protein via exosomes. J Cell Biochem. 2008;104(6):2165–2173.

    Article  CAS  PubMed  Google Scholar 

  44. Gaide Chevronnay HP, Galant C, Lemoine P, Courtoy PJ, Marbaix E, Henriet P. Spatiotemporal coupling of focal extracellular matrix degradation and reconstruction in the menstrual human endometrium. Endocrinology. 2009;150(11):5094–5105.

    Article  PubMed  CAS  Google Scholar 

  45. Kyama CM, Overbergh L, Debrock S, et al. Increased peritoneal and endometrial gene expression of biologically relevant cytokines and growth factors during the menstrual phase in women with endometriosis. Fertil Steril. 2006;85(6):1667–1675.

    Article  CAS  PubMed  Google Scholar 

  46. Rosengren S, Corr M, Boyle DL. Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res Ther. 2010;12(2):R65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Singer CF, Marbaix E, Kokorine I, et al. 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 U S A. 1997;94(19):10341–10345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rawdanowicz TJ, Hampton AL, Nagase H, Woolley DE, Salamonsen LA. 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(2):530–536.

    CAS  PubMed  Google Scholar 

  49. Tabibzadeh S, Sun XZ. Cytokine expression in human endometrium throughout the menstrual cycle. Hum Reprod. 1992;7(9): 1214–1221.

    Article  CAS  PubMed  Google Scholar 

  50. Pretto CM, Gaide Chevronnay HP, Cornet PB, et al. Production of interleukin-1alpha by human endometrial stromal cells is triggered during menses and dysfunctional bleeding and is induced in culture by epithelial interleukin-1alpha released upon ovarian steroids withdrawal. J Clin Endocrinol Metab. 2008;93(10):4126–4134.

    Article  CAS  PubMed  Google Scholar 

  51. Curry TE JrOsteen KG. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol Reprod. 2001;64(5): 1285–1296.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Animal Sciences, University of Illinois, 1207 W. Gregory Drive, 61801, Urbana, IL, USA

    A. G. Braundmeier PhD, C. A. Dayger MS, P. Mehrotra MD, R. J. Belton Jr & R. A. Nowak PhD

  2. Department of Biological Sciences, Northern Michigan University, Marquette, MI, USA

    R. J. Belton Jr

Authors
  1. A. G. Braundmeier PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. A. Dayger MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Mehrotra MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. J. Belton Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. A. Nowak PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. G. Braundmeier PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Braundmeier, A.G., Dayger, C.A., Mehrotra, P. et al. EMMPRIN Is Secreted by Human Uterine Epithelial Cells in Microvesicles and Stimulates Metalloproteinase Production by Human Uterine Fibroblast Cells. Reprod. Sci. 19, 1292–1301 (2012). https://doi.org/10.1177/1933719112450332

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719112450332

Keywords

Search

Navigation