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, 12, 15, 17, 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-10 was higher during murine labor (53-fold vs early pregnancy) in contrast to Mmp-2/3/9 and Timp-1, 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-1]). The Mmp-3/10 and Timp-1 were localized to the uterine epithelium and stroma/myometrium. In the human myometrium, TIMP-1 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-1, and MMP-10 in the uterine ECM remodeling during physiological and pathological parturition.
McCormickMC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med. 1985;312(2):82–90.
2.
GoldenbergRLCulhaneJFIamsJDRomeroR. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.
3.
NormanJEMorrisCChalmersJ. 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.
ManaseKEndoTChidaM. 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.
6.
CockleJVGopichandranNWalkerJJLeveneMIOrsiNM. Matrix metalloproteinases and their tissue inhibitors in preterm perinatal complications. Reprod Sci. 2007;14(7):629–645.
7.
GoldenbergRLHauthJCAndrewsWW. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342(20):1500–1507.
8.
MaymonERomeroRPacoraPGervasiMTGomezR. 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.
9.
FortunatoSJMenonRLombardiSJ. Stromelysins in placental membranes and amniotic fluid with premature rupture of membranes. Obstet Gynecol. 1999;94(3):435–440.
10.
SundraniDChavan-GautamPPisalHMehendaleSJoshiS. 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.
11.
VisseRNagaseH. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–839.
12.
GengJHuangCJiangS. Roles and regulation of the matrix metalloproteinase system in parturition. Mol Reprod Dev. 2016;83(4):276–286.
13.
Gomez-LopezNStLouisDLehrMASanchez-RodriguezENArenas-HernandezM. Immune cells in term and preterm labor. Cell Mol Immunol. 2014;11(6):571–581.
14.
ZhaoYGXiaoAZCaoXMZhuC. Expression of matrix metalloproteinase-2, -9 and tissue inhibitors of metalloproteinase-1, -2, -3 mRNAs in rat uterus during early pregnancy. Mol Reprod Dev. 2002;62(2):149–158.
15.
O’BrienMO’ShaughnessyDAhamideEMorrisonJJSmithTJ. Differential expression of the metalloproteinase MMP3 and the alpha5 integrin subunit in human myometrium at labour. Mol Hum Reprod. 2007;13(9):655–661.
16.
RohCROhWJYoonBKLeeJH. 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.
17.
NguyenTTShynlovaOLyeSJ. Matrix metalloproteinase expression in the rat myometrium during pregnancy, term labor, and postpartum. Biol Reprod. 2016;95(1):24.
18.
RinaldiSFMakievaSFrewL. Ultrasound-guided intrauterine injection of lipopolysaccharide as a novel model of preterm birth in the mouse. Am J Pathol. 2015;185(5):1201–1206.
19.
YangPLiuZWangH. Enhanced activity of very low density lipoprotein receptor II promotes SGC7901 cell proliferation and migration. Life Sci. 2009;84(13-14):402–408.
20.
MenonBSinghMSinghK. Matrix metalloproteinases mediate β-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes. Am J Physiol Cell Physiol. 2005;289(1):168–176.
21.
ShanBMorrisCAZhuoYShelbyBDLevyDRLaskyJA. Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J Mol Cell Cardiol. 2007;42(3):517–525.
22.
PaulSSharmaAVMahapatraPDBhattacharyaPReiterRJSwarnakarS. 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.
23.
VuTDYunFPlacidoJReznikSE. Placental matrix metalloproteinase-1 expression is increased in labor. Reprod Sci. 2008;15(4):420–424.
24.
ChoiSJJungKLOhSYKimJHRohCR. Cervicovaginal matrix metalloproteinase-9 and cervical ripening in human term parturition. Eur J Obstet Gynecol Reprod Biol. 2009;142(1):43–47.
25.
ShynlovaOMitchellJATsampalierosALangilleBLLyeSJ. Progesterone and gravidity differentially regulate expression of extracellular matrix components in the pregnant rat myometrium. Biol Reprod. 2004;70(4):986–992.
26.
SchroenDJBrinckerhoffCE. Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms. Gene Expr. 1996;6(4):197–207.
27.
MesianoSChanECFitterJTKwekKYeoGSmithR. 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.
28.
ZakarTHertelendyF. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol. 2007;196(4):289–296.
29.
CaseyMLMacDonaldPC. The endocrinology of human parturition. Ann NY Acad Sci. 1997;828:273–284.
30.
MesianoS. Myometrial progesterone responsiveness and the control of human parturition. J Soc Gynecol Investig. 2004;11(4):193–202.
31.
LeeYSoorannaSRTerzidouV. 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.
RechardtOElomaaOVaalamoM. Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines. J Invest Dermatol. 2000;115(5):778–787.
34.
Keski-NisulaLTAaltoMLKirkinenPPKosmaVMHeinonenST. Myometrial inflammation in human delivery and its association with labour and infection. Am J Clin Pathol. 2003;120(2):217–224.
35.
HulboyDLRudolphLAMatrisianLM. Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod. 1997;3(1):27–45.
36.
RileySCLeaskRDenisonFCWiselyKCalderAAHoweDC. Secretion of tissue inhibitors of matrix metalloproteinases by human fetal membranes, decidua and placenta at parturition. J Endocrinol. 1999;162(3):351–359.
37.
BrewKNagaseH. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803(1):55–71.
38.
HayakawaT. Tissue inhibitor of metalloproteinases and their cell growth-promoting activity. Cell Struct Funct. 1994;19(3):109.
39.
Stetler-StevensonWG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 2008;1(27):re6.
40.
ParkKHChaiworapongsaTKimYM. 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.
41.
KellerNRSierra-RiveraEEisenbergEOsteenKG. 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.
42.
SoTItoASatoTMoriYHirakawaS. Tumor necrosis factor-alpha stimulates the biosynthesis of matrix metalloproteinases and plasminogen activator in cultured human chorionic cells. Biol Reprod. 1992;46(5):772–778.
43.
WatariMWatariHNachamkinIStraussJF. 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.
44.
PavlovOPavlovaOAilamazyanESelkovS. Characterization of cytokine production by human term placenta macrophages in vitro. Am J Reprod Immunol2008;60(6):556–567.
45.
GonzalezJMFranzkeCWYangFRomeroRGirardiG. Complement activation triggers metalloproteinases release inducing cervical remodeling and preterm birth in mice. Am J Pathol. 2011;179(2):838–849.
46.
JunqueiraLCZugaibMMontesGSToledoOMKrisztanRMShigiharaKM. 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.
47.
Vadillo-OrtegaFHernandezAGonzalez-AvilaGBermejoLIwataKStraussJF 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.
48.
LocksmithGJClarkPDuffPSaadeGRSchultzGS. 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.
49.
AthaydeNEdwinSSRomeroRGomezRMaymonE. A role for matrix metalloproteinase-9 in spontaneous rupture of the fetal membranes. Am J Obstet Gynecol. 1998;179(5):1248–1253.
50.
FortunatoSJMenonRLombardiSJ. 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.
51.
NishiuraRNodaNMinouraH. 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.
52.
HurstPRPalmayRD. Matrix metalloproteinases and their endogenous inhibitors during the implantation period in the rat uterus. Reprod Fertil Dev. 1999;11(7-8):395–402.
53.
DasSKYanoSWangJEdwardsDRNagaseHDeySK. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period. Dev Genet. 1997;21(1):44–54.
54.
ElovitzMWangZ. Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise. Am J Obstet Gynecol. 2004;190(3):693–701.
55.
Guzeloglu-KayisliOKayisliUASemerciN. Mechanisms of chorioamnionitis-associated preterm birth: interleukin-1β inhibits progesterone receptor expression in decidual cells. J Pathol. 2015;237(4):423–434.
56.
MurrayMYBirklandTPHoweJD. Macrophage migration and invasion is regulated by MMP10 expression. PLoS One. 2013;8(5):63–55.
