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Role of Proteases and Their Tissue Inhibitors in Pregnancy Outcome

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Proteases in Health and Disease

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 7))

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Abstract

Mammalian pregnancy is the successful outcome of series of events comprising of effective fertilization of male and female gamete, controlled growth and development of the embryo in the oviduct, transport to the uterus, attachment and implantation in the endometrium. These processes are coordinately and principally regulated by specific steroid hormones, cytokines and growth factors. Recently, matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) have been found to coordinate these events in major ways. They have been found to be involved in folliculogenesis, ovulation, corpus luteum turnover in ovary and degradation and regeneration uterine endometrium (known as endometrial tissue remodeling) during estrous cycle, implantation and placentation that are required for successful pregnancy outcome. The activities of these proteases and their inhibitors change dynamically to release healthy oocytes from ovary and during early pregnancy to render the uterine microenvironment suitable for attachment and implantation of growing embryo and to transform it in to a developed fetus through establishment of feto-maternal circulation. There exists a fine balance between the activities of these proteases and their inhibitors to regulate these events. Any breach in the equilibrium of the proteases and their inhibitors in the ovary or uterine microenvironment or in their regulation may pre-dispose a condition of failed pregnancy. An account of such proteases and their inhibitors and their role in pregnancy outcome has been discussed in this chapter.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Curry TE Jr, Osteen K (2003) The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 24:428–465

    Article  PubMed  CAS  Google Scholar 

  3. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494

    Article  PubMed  CAS  Google Scholar 

  4. Gaide Chevronnay HP, Selvais C, Emonard H et al (2012) Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochem Biophys Acta 1824:146–156

    Article  PubMed  CAS  Google Scholar 

  5. Woessner JF Jr (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154

    PubMed  CAS  Google Scholar 

  6. Nagase H (1997) Activation mechanisms of matrix metalloproteinases. Biol Chem 378:151–160

    PubMed  CAS  Google Scholar 

  7. Rutnam ZJ, Wight TN, Yang BB (2013) miRNAs regulate expression and function of extracellular matrix molecules. Matrix Biol 32(2):74–85, http://dx.doi.org/10.1016/j.matbio.2012.11.003

    Article  PubMed  CAS  Google Scholar 

  8. Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 74:111–122

    PubMed  CAS  Google Scholar 

  9. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477:267–283

    Article  PubMed  CAS  Google Scholar 

  10. Ito Y, Ito H, Nagase H et al (2008) The second dimer interface of MT1-MMP, the transmembrane domain, is essential for ProMP-2 activation on the cell surface. J Biol Chem 283:13053–13062

    Article  PubMed  Google Scholar 

  11. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573

    Article  PubMed  CAS  Google Scholar 

  12. Strickland DK, Ashcom JD, Williams S et al (1990) Sequence identity between the alpha 2-microglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem 265:17401–17404

    PubMed  CAS  Google Scholar 

  13. Bagavandos P (1998) Differential distribution of gelatinases and tissue inhibitor of metalloproteinase-I in the rat ovary. J Endocrinol 158:221–228

    Article  Google Scholar 

  14. Cooke RG, Nothnick C, Komar PD et al (1999) Collagnase and gelatinase messenger ribonucleic acid expression and activity during follicular development in the rat ovary. Biol Reprod 61:1309–1316

    Article  PubMed  CAS  Google Scholar 

  15. Curry TE Jr, Songa L, Wheelera SE (2001) Cellular localization of gelatinases and tissue inhibitors of metalloproteinases during follicular growth, ovulation and early luteal formation in the rat. Biol Reprod 65:855–865

    Article  PubMed  CAS  Google Scholar 

  16. Goldman S, Shalev E (2004) MMPs and TIMPs in ovarian physiology and pathophysiology. Front Biosci 9:2474–2483

    Article  PubMed  CAS  Google Scholar 

  17. Garcia RLM, Ballesteros O, Hernandez-Perez AM et al (1997) Metalloproteinase activity during growth, maturation and atresia in the ovarian follicles of the goat. Anim Reprod Sci 47:211–228

    Article  PubMed  CAS  Google Scholar 

  18. McCaffery FH, Leaskb R, Riley B et al (2000) Culture of bovine preantral follicles in a serum free system: markers for assessment of growth and development. Biol Reprod 63:267–273

    Article  PubMed  CAS  Google Scholar 

  19. Huet CP, Monget C, Pisselet C et al (1998) Chronology of events accompanying follicular atresia in hypophysectomized ewes. Changes in levels of steroidogenic enzymes, connexin 43, insulin-like growth factor II mannose 6 phosphate receptor, extracellular matrix components, and matrix metalloproteinases. Biol Reprod 58:175–185

    Article  PubMed  CAS  Google Scholar 

  20. Peluffo MC, Murphy MJ, Baughman ST et al (2011) Systemic analysis of protease gene expression in the rhesus macaque ovulatory follicle: metalloproteinase involvement in follicle rupture. Endocrinology 152:3963–3974

    Article  PubMed  CAS  Google Scholar 

  21. Smedts AM, Curry TE Jr (2005) Expression of basigin, an inducer of matrix metalloproteinases, in the rat ovary. Biol Reprod 73:80–87

    Article  PubMed  CAS  Google Scholar 

  22. Marbaix E, Kokorine I, Mouline P et al (1996) Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases. Proc Natl Acad Sci U S A 93:9120–9125

    Article  PubMed  CAS  Google Scholar 

  23. Goffin F, Munaut C, Frankenne F, d’Hauterive SP, Beliard A, Fridman V, Nervo P, Colige A, Foidart J (2003) Expression pattern of metalloproteinases and tissue inhibitors of matrix-metalloproteinases in cycling human endometrium. Biol Reprod 69:976–984

    Article  PubMed  CAS  Google Scholar 

  24. Hampton AL, Salamonsen LA (1994) Expression of messenger ribonucleic acid encoding matrix metalloproteinases and their tissue inhibitors is related to menstruation. J Endocrinol 141:R1–R3

    Article  PubMed  CAS  Google Scholar 

  25. Pilka R, Noskova V, Domanski H et al (2006) Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid. Mol Hum Reprod 8:497–503

    Article  Google Scholar 

  26. 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

    Article  PubMed  CAS  Google Scholar 

  27. Jeziorska M, Nagase H, Salamonsen LA, Woolley DE (1996) Immunolocalization of the matrix metalloproteinases gelatinase B and stromelysin-1 in human endometrium throughout the menstrual cycle. J Reprod Fertil 107:43–51

    Article  PubMed  CAS  Google Scholar 

  28. Kang T, Yi J, Guo A et al (2001) Subcellular distribution and cytokine- and chemokine-regulated secretion of leukolysin/MT6-MMP/MMP-25 in neutrophils. J Biol Chem 276:21960–21968

    Article  PubMed  CAS  Google Scholar 

  29. Rogers WH, Osteen KG, Matrisian LM, Giudice LC, Dsupin B, Cannon P, Svitek C, Gorstein F, Osteen KG (1994) Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest 94:946–953

    Article  Google Scholar 

  30. Kokorin I, Marbaix E, Henriet P et al (1996) Focal cellular origin and regulation of interstitial collagenase (matrix metalloproteinase-1) are related to menstrual breakdown in the human endometrium. J Cell Sci 109:2151–2160

    Google Scholar 

  31. Zhang J, Salamonsen LA (2002) In vivo evidence for active matrix metalloproteinases in human endometrium supports their role in tissue breakdown at menstruation. J Clin Endocrinol Metab 87:2346–2351

    Article  PubMed  CAS  Google Scholar 

  32. Lockwood CJ, Krikun G, Hausknecht VA et al (1998) Matrix metalloproteinase and matrix metalloproteinase inhibitor expression in endometrial stromal cells during progestin-initiated decidualization and menstruation-related progestin withdrawal. Endocrinology 139:4607–4613

    Article  PubMed  CAS  Google Scholar 

  33. Marbaix E, Donnez J, Courtoy PJ et al (1992) Progesterone regulates the activity of collagenase and related gelatinase A and B in human endometrial explants. Proc Natl Acad Sci U S A 89:11789–11793

    Article  PubMed  CAS  Google Scholar 

  34. Osteen KG, Rodgers WH, Gaire M et al (1994) Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci U S A 91:10129–10133

    Article  PubMed  CAS  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

  36. Hampton AL, Butt AR, Riley SC, Salamonsen LA (1995) Tissue inhibitors of metalloproteinases in endometrium of ovariectomized steroid-treated ewes and during the estrous cycle and early pregnancy. Biol Reprod 53:302–311

    Article  PubMed  CAS  Google Scholar 

  37. Salamonsen LA, Nagase H, Woolley DE (1995) Matrix metalloproteinases and their tissue inhibitors at the ovine trophoblast-uterine interface. J Reprod Fertil Suppl 49:29–37

    PubMed  CAS  Google Scholar 

  38. Hashizume K, Takahashi T, Shimizu M, Todoroki J, Shimada A, Hirata M, Sato T, Ito A (2003) Matrix metalloprotenases-2 and -9 production in bovine endometrial cell culture. J Reprod Dev 49:45–53

    Article  PubMed  CAS  Google Scholar 

  39. Hirata M, Sato T, Tsumagari M, Shimada A, Nakano H, Hashizume K, Ito A (2003) Differential regulation of the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases by cytokines and growth factors in bovine endometrial stromal cells and trophoblast cell line BT-1 in vitro. Biol Reprod 68:1276–1281

    Article  PubMed  CAS  Google Scholar 

  40. Ghosh D, Najwa AR, Khan MA et al (2011) IGF2, IGF binding protein 1, and matrix metalloproteinases 2 and 9 in implantation-stage endometrium following immunoneutralization of vascular endothelial growth factor in the rhesus monkey. Reproduction 141:501–509

    Article  PubMed  CAS  Google Scholar 

  41. Pollete M, Nawrocki B, Pintiaux A, Massenat C, Maquoi E, Volders L, Schaaps JP, Birembaut P, Foidart JM (1994) Expression of gelatinases A and B and their tissue inhibitors by cells of early and term human placenta and gestational endometrium. Lab Invest 71:838–846

    Google Scholar 

  42. Sharkey ME, Adler RR, Nieder GL, Brenner CA (1996) Matrix metalloproteinase expression during mouse peri-implantation development. Am J Reprod Immunol 36:72–80

    Article  PubMed  CAS  Google Scholar 

  43. Maj JG, Kankfer M (1997) Activity of 72-kDa and 92-kDa matrix metalloproteinases in placental tissues of cows with and without retained fetal membranes. Placenta 18:683–687

    Article  PubMed  CAS  Google Scholar 

  44. Walter I, Boos A (2001) Matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor-2 of matrix metalloproteinases (TIMP-2) in the placenta and interplacental uterine wall in normal cows and in cattle with retention of fetal membranes. Placenta 22:473–483

    Article  PubMed  CAS  Google Scholar 

  45. Roy SC, Ghosh J (2010) Dynamic in vivo changes in the activities of gelatinases, matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases (TIMPs) in buffalo (Bubalus bubalis) uterine luminal fluid during estrous cycle and early pregnancy. Mol Reprod Dev 77:944–953

    Article  PubMed  CAS  Google Scholar 

  46. Bischof P, Meisser A, Campana A (2000) Mechanisms of endometrial control of trophoblast invasion. J Reprod Fertil Suppl 55:65–71

    PubMed  CAS  Google Scholar 

  47. Wooding FBP (1992) Current topic: the synepitheliochorial placenta of ruminants; binucleate cell fusion and hormone production. Placenta 13:101–113

    Article  PubMed  CAS  Google Scholar 

  48. Kizaki K, Ushizawa K, Takahashi T, Yamada O, Todoroki J, Sato T, Ito A, Hashizume K (2008) Gelatinase (MMP-2 and -9) expression profiles during gestation in the bovine endometrium. Reprod Biol Endocrinol 6:66

    Article  PubMed  Google Scholar 

  49. Ledgard AM, Lee RSF, Peterson AJ (2009) Bovine endometrial legmain and TIMP-2 regulation in response to presence of a conceptus. Mol Reprod Dev 76:65–74

    Article  PubMed  CAS  Google Scholar 

  50. Horka P, Malickova K, Jarosova R et al (2012) Matrix metalloproteinases in serum and the follicular fluid of women treated by in vitro fertilization. J Assist Reprod Genet 11:1207–1212

    Article  Google Scholar 

  51. Jokimaa V, Oksjoki S, Kujari H et al (2002) Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriage. Mol Hum Reprod 8:1111–1116

    Article  PubMed  CAS  Google Scholar 

  52. Salata IM, Stojanovic N, Cajdler-Luba A et al (2008) Gelatinase A (MMP-2), gelatinase B (MMP-9) and their inhibitors (TIMP-1, TIMP-2) in serum of women with endometriosis: significant correlation between MMP-2, MMP-9 and their inhibitors without difference in levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in relation to the severity of endometriosis. Gynecol Endocrinol 24:326–330

    Article  PubMed  CAS  Google Scholar 

  53. Skrzypczak J, Wirstlein P, Mikolajczyk M (2007) Could the defects in the endometrial extracellular matrix during the implantation be a cause for impaired fertility? Am J Reprod Immunol 57:40–48

    Article  PubMed  Google Scholar 

  54. Konac E, Alp E, Onen HI et al (2009) Endometrial mRNA expression of matrix metalloproteinases, their tissue inhibitors and cell adhesion molecules in unexplained infertility and implantation failure patients. Reprod Biomed Online 3:391–397

    Article  Google Scholar 

  55. Anumba DO, El Gelany S, Elliot SL et al (2010) Circulating levels of matrix proteases and their inhibitors in pregnant women with and without a history of recurrent pregnancy loss. Reprod Biol Endocrinol 8:62

    Article  PubMed  Google Scholar 

  56. Pereza N, Ostojic S, Volk M et al (2012) Matrix metalloproteinases 1, 2, 3, and 9 functional single nucleotide polymorphisms in idiopathic recurrent spontaneous abortion. Reprod Biomed Online 24:567–575

    Article  PubMed  CAS  Google Scholar 

  57. 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

    Article  PubMed  CAS  Google Scholar 

  58. Shalev E, Goldman S, Ben-Shlomo I (2001) The balance between MMP-9 and MMP-2 and their tissue inhibitor (TIMP)-1 in luteinized granulosa cells: comparison between women with PCOS and normal ovulatory women. Mol Hum Reprod 7:325–331

    Article  PubMed  CAS  Google Scholar 

  59. Gomes VA, Vieira CS, Jacob-Ferreira AL (2011) Imbalanced circulating matrix metalloproteinases in polycystic ovary syndrome. Mol Cell Biochem 353:251–257

    Article  PubMed  CAS  Google Scholar 

  60. Baka S, Zouria K, Kouskouni E et al (2010) Matrix metalloproteinases 2 and 9 and their tissue inhibitors in the follicular fluid of patients with polycystic ovaries undergoing in vitro fertilization. In Vivo 24:293–296

    PubMed  CAS  Google Scholar 

  61. Stilley JA, Brit JA, Nagel SC et al (2010) Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development. Biol Reprod 83:185–194

    Article  PubMed  CAS  Google Scholar 

  62. Stilley JA, Sharpe-Timms KL (2012) TIMP1 contributes to ovarian anomalies in both an MMP-dependent and -independent manner in a rat model. Biol Reprod 86:47. doi:10.1095/biolreprod.111.094680

    Article  PubMed  Google Scholar 

  63. Zhang X, Qi C, Lin J (2010) Enhanced expression of matrix metalloproteinase (MMP)-2 and -9 and vascular endothelial growth factors (VEGF) and increased microvascular density in the endometrial hyperplasia of women with anovulatory dysfunctional uterine bleeding. Fertil Steril 93:2362–2367

    Article  PubMed  CAS  Google Scholar 

  64. Gallery ED, Campbell S, Arkell J et al (1999) Preeclamptic decidual microvascular endothelial cells express lower levels of matrix metalloproteinase-1 than normals. Microvasc Res 57:340–346

    Article  PubMed  CAS  Google Scholar 

  65. Pang ZJ, Xing FQ (2003) Expression profile of trophoblast invasion-associated genes in the pre-eclamptic placenta. Br J Biomed Sci 60:97–101

    PubMed  CAS  Google Scholar 

  66. Tency I, Verstraelen H, Kroes I et al (2012) Imbalances between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in maternal serum during preterm labor. PLoS One 7(11):e49042

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The study was supported by grant from Indian Council of Agricultural Research (ICAR), New Delhi-110001, Government of India. The author thank the Director, National Institute of Animal Nutrition and Physiology, Bangalore, India for providing funds and facilities for carrying out the present study.

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Correspondence to Sudhir C. Roy .

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Roy, S.C. (2013). Role of Proteases and Their Tissue Inhibitors in Pregnancy Outcome. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Health and Disease. Advances in Biochemistry in Health and Disease, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9233-7_16

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