Skip to main content
SpringerLink
Log in

Expression of Matrix Metalloproteinases in the Mouse Uterus and Human Myometrium During Pregnancy, Labor, and Preterm Labor

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

Abstrct

Background

Uterine extracellular matrix (ECM) remodeling occurs throughout pregnancy and at parturition. Imbalanced availability of key mediators in ECM degradation, namely, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), is implicated in the pathogenesis of preterm labor (PTL).

Objectives

Examine the expression of MMPs and their inhibitors TIMPs in (a) the mouse uterus throughout normal gestation, at labor, and during inflammation-induced PTL and (b) the human term and preterm myometrium.

Methods

The expression of Mmp-2/9/3/10 and Timp-1/2 was determined in the uterus of C57BL/6 mice (n — 6/group) during pregnancy (on days (d) 5, 8, I 2, 15, I 7, and 18), at normal labor, and during lipopolysaccharide-induced PTL (n — 6/group). The expression of MMP-10 and TIMP-1 was determined in human term and preterm myometrium before the onset of labor (TNL, n = 7; PTNL, n = 7) and during active labor (TL, n = 8; PTL, n — 8). Gene expression and tissue localization were assessed by quantitative polymerase chain reaction and immunohistochemistry, respectively.

Results

Mmp-IO was higher during murine labor (53-fold vs early pregnancy) in contrast to Mmp-21319 and Timp-I, the expression of which reached a nadir at labor (P <.001 vs d5 [Mmp-2/9] or P <.05 vs d8 [Mmp-3 and Timp-I]). The Mmp-3/10 and Timp-I were localized to the uterine epithelium and stroma/myometrium. In the human myometrium, TIMP-I messenger RNA was higher and MMP-10 was lower in TL versus TNL (P <.05), PTL (P <.001), and PTNL (P <.001). MMP-10 and TIMP-1 were localized to the myometrial smooth muscle cells, interstitial fibroblasts, and inflammatory cells. Conclusions: These data implicate MMP-3, TIMP-I, and MMP-IO in the uterine ECM remodeling during physiological and pathological parturition.

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

References

  1. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med. 1985;312(2): 82–90.

    Article  CAS  PubMed  Google Scholar 

  2. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Norman JE, Morris C, Chalmers J. The effect of changing patterns of obstetric care in Scotland (1980–2004) on rates of preterm birth and its neonatal consequences: perinatal database study. PLoS Med. 2009;6(9):e1000153.

    Google Scholar 

  4. Monga M, Sanborn BM. Uterine contractile activity. Introduction. Semin Perinatol. 1995;19:1–2.

    Article  CAS  PubMed  Google Scholar 

  5. Manase K, Endo T, Chida M, et al. Coordinated elevation of membrane type 1-matrix metalloproteinase and matrix metalloproteinase-2 expression in rat uterus during post-partum involution. Reprod Biol Endocrinol. 2006;4:32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Cockle JV, Gopichandran N, Walker JJ, Levene MI, Orsi NM. Matrix metalloproteinases and their tissue inhibitors in preterm perinatal complications. Reprod Sci. 2007;14(7):629–645.

    Article  CAS  PubMed  Google Scholar 

  7. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342(20):1500–1507.

    Article  CAS  PubMed  Google Scholar 

  8. Maymon E, Romero R, Pacora P, Gervasi MT, Gomez R. Evidence of in vivo differential bioavailability of the active forms of matrix metalloproteinases 9 and 2 in parturition, spontaneous rupture of membranes, and intraamniotic infection. Am J Obstet Gynecol. 2000;183(4):887–894.

    Article  CAS  PubMed  Google Scholar 

  9. Fortunato SJ, Menon R, Lombardi SJ. Stromelysins in placental membranes and amniotic fluid with premature rupture of membranes. Obstet Gynecol. 1999;94(3):435–440.

    CAS  PubMed  Google Scholar 

  10. Sundrani D, Chavan-Gautam P, Pisal H, Mehendale S, Joshi S. Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites. Reproduction. 2013;145(4):401–410.

    Article  CAS  PubMed  Google Scholar 

  11. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–839.

    Article  CAS  PubMed  Google Scholar 

  12. Geng J, Huang C, Jiang S. Roles and regulation of the matrix metalloproteinase system in parturition. Mol Reprod Dev. 2016; 83(4):276–286.

    Article  CAS  PubMed  Google Scholar 

  13. Gomez-Lopez N, StLouis D, Lehr MA, Sanchez-Rodriguez EN, Arenas-Hernandez M. Immune cells in term and preterm labor. Cell Mol Immunol. 2014;11(6):571–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhao YG, Xiao AZ, Cao XM, Zhu C. Expression of matrix metalloproteinase-2, -9 and tissue inhibitors of Lombardi et al 947 metalloproteinase-1, -2, -3 mRNAs in rat uterus during early pregnancy. Mol Reprod Dev. 2002;62(2):149–158.

    Article  CAS  PubMed  Google Scholar 

  15. O’Brien M, O’Shaughnessy D, Ahamide E, Morrison JJ, Smith TJ. Differential expression of the metalloproteinase MMP3 and the alpha5 integrin subunit in human myometrium at labour. Mol Hum Reprod. 2007;13(9):655–661.

    Article  PubMed  CAS  Google Scholar 

  16. Roh CR, Oh WJ, Yoon BK, Lee JH. Up-regulation of matrix metalloproteinase-9 in human myometrium during labour: a cytokine-mediated process in uterine smooth muscle cells. Mol Hum Reprod. 2000;6(1):96–102.

    Article  CAS  PubMed  Google Scholar 

  17. Nguyen TT, Shynlova O, Lye SJ. Matrix metalloproteinase expression in the rat myometrium during pregnancy, term labor, and postpartum. Biol Reprod. 2016;95(1):24.

    Google Scholar 

  18. Rinaldi SF, Makieva S, Frew L, et al. Ultrasound-guided intrauterine injection of lipopolysaccharide as a novel model of preterm birth in the mouse. Am J Pathol. 2015;185(5):1201–1206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang P, Liu Z, Wang H. Enhanced activity of very low density lipoprotein receptor II promotes SGC7901 cell proliferation and migration. Life Sci. 2009;84(13-14):402–408.

    Article  CAS  PubMed  Google Scholar 

  20. Menon B, Singh M, Singh K. Matrix metalloproteinases mediate b-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes. Am J Physiol Cell Physiol. 2005;289(1):168–176.

    Article  CAS  Google Scholar 

  21. Shan B, Morris CA, Zhuo Y, Shelby BD, Levy DR, Lasky JA. Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J Mol Cell Cardiol. 2007; 42(3):517–525.

    Article  CAS  PubMed  Google Scholar 

  22. Paul S, Sharma AV, Mahapatra PD, Bhattacharya P, Reiter RJ, Swarnakar S. Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis. J Pineal Res. 2008; 44(4):439–449.

    Article  CAS  PubMed  Google Scholar 

  23. Vu TD, Yun F, Placido J, Reznik SE. Placental matrix metalloproteinase-1 expression is increased in labor. Reprod Sci. 2008;15(4):420–424.

    Article  CAS  PubMed  Google Scholar 

  24. Choi SJ, Jung KL, Oh SY, Kim JH, Roh CR. Cervicovaginal matrix metalloproteinase-9 and cervical ripening in human term parturition. Eur J Obstet Gynecol Reprod Biol. 2009;142(1): 43–47.

    Article  CAS  PubMed  Google Scholar 

  25. Shynlova O, Mitchell JA, Tsampalieros A, Langille BL, Lye SJ. Progesterone and gravidity differentially regulate expression of extracellular matrix components in the pregnant rat myometrium. Biol Reprod. 2004;70(4):986–992.

    Article  CAS  PubMed  Google Scholar 

  26. Schroen DJ, Brinckerhoff CE. Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms. Gene Expr. 1996;6(4):197–207.

    CAS  PubMed  Google Scholar 

  27. Mesiano S, Chan EC, Fitter JT, Kwek K, Yeo G, Smith R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor a expression in the myometrium. J Clin Endocrinol Metab. 2002;87(6):2924–2930.

    Article  CAS  PubMed  Google Scholar 

  28. Zakar T, Hertelendy F. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol. 2007;196(4):289–296.

    Article  CAS  PubMed  Google Scholar 

  29. Casey ML, MacDonald PC. The endocrinology of human parturition. Ann NY Acad Sci. 1997;828:273–284.

    Google Scholar 

  30. Mesiano S. Myometrial progesterone responsiveness and the control of human parturition. J Soc Gynecol Investig. 2004;11(4): 193–202.

    Article  CAS  PubMed  Google Scholar 

  31. Lee Y, Sooranna SR, Terzidou V, et al. Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes. J Cell Mol Med. 2012;16(10):2487–2503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lei K, Chen L, Cryar BJ, et al. Uterine stretch and progesterone action. J Clin Endocrinol Metab. 2011;96(6):E1013-E1024.

    Google Scholar 

  33. Rechardt O, Elomaa O, Vaalamo M, et al. Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines. J Invest Dermatol. 2000;115(5):778–787.

    Article  CAS  PubMed  Google Scholar 

  34. Keski-Nisula LT, Aalto ML, Kirkinen PP, Kosma VM, Heinonen ST. Myometrial inflammation in human delivery and its association with labour and infection. Am J Clin Pathol. 2003;120(2): 217–224.

    Article  PubMed  Google Scholar 

  35. Hulboy DL, Rudolph LA, Matrisian LM. Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod. 1997;3(1):27–45.

    Article  CAS  PubMed  Google Scholar 

  36. Riley SC, Leask R, Denison FC, Wisely K, Calder AA, Howe DC. Secretion of tissue inhibitors of matrix metalloproteinases by human fetal membranes, decidua and placenta at parturition. J Endocrinol. 1999;162(3):351–359.

    Article  CAS  PubMed  Google Scholar 

  37. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803(1):55–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hayakawa T. Tissue inhibitor of metalloproteinases and their cell growth-promoting activity. Cell Struct Funct. 1994;19(3):109.

    Google Scholar 

  39. Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 2008;1(27):re6.

    Google Scholar 

  40. Park KH, Chaiworapongsa T, Kim YM, et al. Matrix metalloproteinase 3 in parturition, premature rupture of the membranes, and microbial invasion of the amniotic cavity. J Perinat Med. 2003; 31(1):12–22.

    Article  CAS  PubMed  Google Scholar 

  41. Keller NR, Sierra-Rivera E, Eisenberg E, Osteen KG. Progesterone exposure prevents matrix metalloproteinase-3 (MMP-3) stimulation by interleukin-1alpha in human endometrial stromal cells. J Clin Endocrinol Metab. 2000;85(4):1611–1619.

    CAS  PubMed  Google Scholar 

  42. So T, Ito A, Sato T, Mori Y, Hirakawa S. Tumor necrosis factoralpha stimulates the biosynthesis of matrix metalloproteinases and plasminogen activator in cultured human chorionic cells. Biol Reprod. 1992;46(5):772–778.

    Article  CAS  PubMed  Google Scholar 

  43. Watari M, Watari H, Nachamkin I, Strauss JF. Lipopolysaccharide induces expression of genes encoding pro-inflammatory cytokines and the elastin-degrading enzyme, cathepsin S, in human cervical smooth-muscle cells. J Soc Gynecol Investig. 2000;7(3): 190–198.

    Article  CAS  PubMed  Google Scholar 

  44. Pavlov O, Pavlova O, Ailamazyan E, Selkov S. Characterization of cytokine production by human term placenta macrophages in vitro. Am J Reprod Immunol 2008;60(6):556–567.

    Article  PubMed  Google Scholar 

  45. Gonzalez JM, Franzke CW, Yang F, Romero R, Girardi G. Complement activation triggers metalloproteinases release inducing cervical remodeling and preterm birth in mice. Am J Pathol. 2011;179(2):838–849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Junqueira LC, Zugaib M, Montes GS, Toledo OM, Krisztan RM, Shigihara KM. Morphologic and histochemical evidence for the occurrence of collagenolysis and for the role of neutrophilic polymorphonuclear leukocytes during cervical dilation. Am J Obstet Gynecol. 1980;138(3):273–281.

    Article  CAS  PubMed  Google Scholar 

  47. Vadillo-Ortega F, Hernandez A, Gonzalez-Avila G, Bermejo L, Iwata K, Strauss JF III. Increased matrix metalloproteinase activity and reduced tissue inhibitor of metalloproteinases-1 levels in amniotic fluids from pregnancies complicated by premature rupture of membranes. Am J Obstet Gynecol. 1996;174(4):1371–1376.

    Article  CAS  PubMed  Google Scholar 

  48. Locksmith GJ, Clark P, Duff P, Saade GR, Schultz GS. Amniotic fluid concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 during pregnancy and labor. Am J Obstet Gynecol. 2001;184(2):159–164.

    Article  CAS  PubMed  Google Scholar 

  49. Athayde N, Edwin SS, Romero R, Gomez R, Maymon E. A role for matrix metalloproteinase-9 in spontaneous rupture of the fetal membranes. Am J Obstet Gynecol. 1998;179(5):1248–1253.

    Article  CAS  PubMed  Google Scholar 

  50. Fortunato SJ, Menon R, Lombardi SJ. MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture. J Perinat Med. 1999;27(5): 362–368.

    Article  CAS  PubMed  Google Scholar 

  51. Nishiura R, Noda N, Minoura H, et al. Expression of matrix metalloproteinase-3 in mouse endometrial stromal cells during early pregnancy: regulation by interleukin-1alpha and tenascin- C. Gynecol Endocrinol. 2005;21(2):111–118.

    Article  CAS  PubMed  Google Scholar 

  52. Hurst PR, Palmay RD. Matrix metalloproteinases and their endogenous inhibitors during the implantation period in the rat uterus. Reprod Fertil Dev. 1999;11(7-8):395–402.

    Article  CAS  PubMed  Google Scholar 

  53. Das SK, Yano S, Wang J, Edwards DR, Nagase H, Dey SK. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the periimplantation period. Dev Genet. 1997;21(1):44–54.

    Article  CAS  PubMed  Google Scholar 

  54. Elovitz M, Wang Z. Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise. Am J Obstet Gynecol. 2004;190(3): 693–701.

    Article  CAS  PubMed  Google Scholar 

  55. Guzeloglu-Kayisli O, Kayisli UA, Semerci N, et al. Mechanisms of chorioamnionitis-associated preterm birth: interleukin-1μ inhibits progesterone receptor expression in decidual cells. J Pathol. 2015;237(4):423–434.

    Article  CAS  PubMed  Google Scholar 

  56. Murray MY, Birkland TP, Howe JD, et al. Macrophage migration and invasion is regulated by MMP10 expression. PLoS One. 2013;8(5):63–55.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Developmental Medicine, University of Siena, Policlinico “Santa Maria alle Scotte,”, Viale Bracci, 53100, Siena, Italy

    Annalia Lombardi PhD, Felice Arcuri PhD & Felice Petraglia MD

  2. Tommy’s Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

    Sofia Makieva PhD, Sara F. Rinaldi PhD & Jane E. Norman MD

Authors
  1. Annalia Lombardi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sofia Makieva PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara F. Rinaldi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Felice Arcuri PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Felice Petraglia MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jane E. Norman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annalia Lombardi PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lombardi, A., Makieva, S., Rinaldi, S.F. et al. Expression of Matrix Metalloproteinases in the Mouse Uterus and Human Myometrium During Pregnancy, Labor, and Preterm Labor. Reprod. Sci. 25, 938–949 (2018). https://doi.org/10.1177/1933719117732158

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719117732158

Keywords

Search

Navigation