Molecular Human Reproduction, Vol. 7, No. 12, 1187-1193,
December 2001
© 2001 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
Matrix metalloproteinase (MMP)-2 and MMP-9 and their inhibitor, TIMP-1, in human term decidua and fetal membranes: the effect of prostaglandin F2
and indomethacin
1 Laboratory for Research in Reproductive Sciences, Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula and 2 Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
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Abstract |
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Degradation and breakdown of gestational membranes and the adjacent decidua are essential processes for the advancement of labour. We have assessed the effect of prostaglandin (PG) synthesis on the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and tissue inhibitor of metalloproteinases (TIMP-1) in fetal membranes at the edge of the placenta and decidua, by using ex-vivo organ culture of the tissues in the absence or presence of PGF2
(0.1, 1.0 and 10 µg/ml) or a PG synthesis inhibitor, indomethacin (10–4–10–6 mol/l). Conditioned media were assessed for MMP by zymography on gelatin containing sodium dodecyl sulphate–polyacrylamide gels and for TIMP-1 by Western blot analysis. Compared to the membranes, decidua produced significantly more MMP-2 and MMP-9 as well as TIMP-1. PGF2 caused a 2.4- and 1.9-fold increase in the production of MMP-2 and MMP-9 in the decidua, respectively (P < 0.05), and an 11.3-fold increase of the active form of MMP-2 (62 kDa) which could hardly be detected in basal culture conditions (P < 0.01). PGF2 decreased TIMP-1 production by 70% in the decidua. The production of MMP-2 and MMP-9 and TIMP-1 by the amniotic and chorionic membranes was not affected by PGF2. Indomethacin decreased the production of MMP-2 and MMP-9 by 78 and 35% in chorion, and by 70 and 58% in amnion, respectively (P < 0.05), but did not affect production in decidual tissue. Indomethacin increased the production of TIMP-1 in chorion and amnion [by 4.1- and 4.5-fold respectively (P < 0.01)], but had no effect on decidua. Cumulatively, PGF2 increases decidual gelatinolytic activity. Meanwhile the inhibition of PG production by indomethacin reduces total gelatinolytic activity in fetal membranes, possibly accounting for some of its labour-arresting property.
fetal membranes/indomethacin/matrix metalloproteinase/prostaglandin F2/TIMP-1
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Introduction |
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The physiological ending of human gestation is marked by the initiation of uterine contractions or by amniotic membrane rupture after ~265 days from conception. Degradation and breakdown of gestational membranes (chorion and amnion) and the adjacent decidua are essential processes for the advancement of labour. However, if these sequential events would occur before the designated time or later than the expected period, newborns face adverse consequences of prematurity or post-term delivery respectively. Hence tocolytic agents which attenuate uterine contractions in threatened preterm deliveries or uterotonic agents which stimulate labour in post-term pregnancies are in daily use (Zlatnik, 1999
; Thorp et al., 2000). Prostaglandins (PG), which are known mediators in the propagation of labour, act most pronouncedly on cervical structure and consistency but also induce myometrial contractions (Olson et al., 1983) and membrane rupture. At the same time, medications that block prostaglandin synthesis, such as indomethacin, have been used for the prevention of preterm labour (Zuckerman et al., 1984a,b; Gyetvai et al., 1999).
Alongside and in conjunction with PG, a series of extracellular collagenolytic enzymes, called matrix metalloproteinases (MMP) has been implicated in the propagation of labour, either at term or preterm (Vadillo-Ortega et al., 1995). Specifically, gelatinase A (MMP-2) and gelatinase B (MMP-9) have been studied in this context, owing to the fact that they degrade collagen types 1, 4 and 5 (Athayde et al., 1998; Lei et al., 1999). The three layers of fetal–maternal interface, i.e. amnion, chorion and decidua, contain extracellular matrix (ECM), which is composed of several types of collagen and provides mechanical strength to the tissues. Specifically, collagen types 1, 4 and 5 are components of ECM in gestational membranes (Hampson et al., 1997; Shandley et al., 1997). It has been found that, in addition to the MMP, decidua and fetal membranes express all four known types of tissue inhibitors of MMP (TIMP) during parturition (Fortunato et al., 1997, 1998; Riley et al., 1999). To this has been added the observation that the ratio between MMP-9 and TIMP-1 indeed correlates with the tensile strength of the fetal membranes (Uchide et al., 2000). All inflamed tissues show increased collagenolytic activity concurrent with robust activation of arachidonic acid metabolism, resulting in the production of PG. Several in-vitro studies have demonstrated a relationship between the elaboration of inflammatory cytokines and the increased activity of MMP (Saito et al., 1998). Further studies have established a cascade of events, leading from cytokines to production of PG and subsequent expression of MMP (Lindsey et al., 1997; Zahner et al., 1997), although others do not agree (Rath et al., 1987). Both PG and MMP have been known to increase during human parturition, but their possible functional interdependence was only recently addressed. These recent findings indicate that PG play a role in the up-regulation of MMP during labour (McLaren et al., 2000). However, the studies that have examined MMP expression and activity at the fetal–maternal interface have not clearly separated the three tissue compartments (Vadillo-Ortega et al., 1995; Athayde et al., 1998; Rath et al., 1998; Riley et al., 1999; Tsatas et al., 1999).
In order to asses the possible effect of prostaglandin synthesis on the expression and activity of MMP-2, MMP-9 and TIMP-1 in fetal and maternal membranes from term deliveries, we exposed ex-vivo organ cultures of the three layers to both exogenous PGF2 and the prostaglandin synthase inhibitor, indomethacin.
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Materials and methods |
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Patients
Chorion, amnion and decidua were collected from 16 women delivered by scheduled repeat elective Caesarean section in the Department of Obstetrics and Gynecology at Ha'Emek Medical Center, Afula, Israel. Ethical approval was obtained from the hospital's IRB and informed consent was obtained from the patients. These individuals had uncomplicated, singleton, term (38–39 completed weeks) pregnancies and were operated on prior to the establishment of regular uterine contractions or rupture of membranes. No sampled specimens presented any clinical or microbiological sign of infection.
Collection of samples
All specimens were collected in aseptic conditions in the operating suite. Once the newborn was delivered during the Caesarean section, the placenta was manually removed and taken in a sterile sheet. Superficial amniotic membrane was gently separated from an area above the chorionic plate. The chorionic tissue sample was then taken from the denuded area underneath, where the chorion turns from placenta to a membrane. This enabled sampling of membranal chorionic tissue without decidual contamination. A sample was taken from the decidua vera (away from the placental implantation site) by scissors after removal of the placenta. Following collection, tissue samples were immediately immersed in pre-warmed artificial substitute to human tubal fluid medium without serum (HTF; Irvine Scientific, CA, USA). The remaining tissue handling was performed under a laminar flow hood. All specimens were washed with HTF to remove the remaining blood before the beginning of the incubation period.
Preparation of samples
Blocks of similar size (~0.5 cm x 0.5 cm) samples were dissected from each tissue type. Incubations of samples were performed in the absence or presence of 0.1, 1.0 or 10 µg/ml PGF2 (Prostin F2 alpha; Pharmacia and Upjohn, Belgium) or indomethacin 10–6–10–4 mol/l (Indoptic; Merck Sharp and Dohme BV, The Netherlands). For each tissue, four samples including the control were incubated within 0.5 ml HTF in 1.7 ml conical tubes with perforated cap, to allow free exchange of gases. Incubation was in a 37°C humidified incubator with 95% air and 5% CO2. After conclusion of the specified period of incubation, the media were collected and final fluid volumes were measured. The final wet weight of the corresponding tissue block was also determined. All media were then stored in –20°C until assay. Electrophoresis assays were performed using media conditioned by 1.0 mg tissue, except for experiments in which a robust production of MMP was expected (in which case a reduced amount was used). This was usually 10–30 µl of conditioned medium.
Substrate gel electrophoresis (zymography)
In order to detect proteolytic activity in conditioned media, substrate gel electrophoresis (zymography) on gels containing gelatin as the substrate were used. Conditioned media molecular mass markers (10 µl), and standard commercial gelatinases A and B (7 µl; Oncogene Science, Cambridge, MA, USA) were diluted with 4x sample buffer [5% sodium dodecyl sulphate (SDS), 20% glycerol in 0.4 mol/l Tris, pH 6.8 containing 0.02% Bromophenol Blue without 2-mercaptoethanol]. Samples were electrophoresed through a 10% polyacrylamide gel containing 0.5% gelatin (50 mg/ml). After electrophoresis, gelatin gels were washed twice in 2.5% Triton X-100 for 15 min. Gelatin gels were incubated for 24 h at 37°C in 0.2 mol/l NaCl, 5 mmol/l CaCl2, 0.02% Brij 35 and 50 mmol/l Tris, pH 7.5. The buffer was decanted and the gel stained with Coomassie Blue G in 30% methanol and 10% acetic acid for 10 min at room temperature on a rotary shaker. Stain was washed out with water until clear bands were seen. Finally, the gel was incubated for 30 min in 45% methanol, 5% glycerol prior to drying overnight between stretched sheets of cellophane. Areas where proteolytic activity degraded the gelatin were seen as absence of staining. These were quantified using the BioImaging gel documentation system (Dinco & Renium, Jerusalem, Israel) endowed with TINA software (Raytest, Staubenhardt, Germany). In addition, a validation/inhibition study with 10 mmol/l EDTA was performed (data not shown). This procedure chelates the Zn2+ at the active site of MMP and inhibits their activity (Rao et al., 1995).
Western blot analysis
In order to detect TIMP-1, conditioned media and molecular mass markers (10 µl) were diluted with 4x sample buffer (5% SDS, 20% glycerol in 0.4 mol/l Tris, pH 6.8 containing 0.02% Bromophenol Blue without 2-mercaptoethanol) and subjected to 10% polyacrylamide gel electrophoresis (PAGE). After electrophoresis, the proteins (50 µg/lane) were blotted from the SDS–PAGE onto 0.45 µm nitrocellulose membranes (Scheicher & Schuel, Dassel, Germany). Non-specific binding sites were blocked by incubating the nitrocellulose membranes overnight with 20% non-fat milk and Tris-buffered saline, containing 0.01% Tween-20. The membranes were then washed twice with Tris-buffered saline, containing 0.5% Tween-20, and incubated for 1 h with mouse anti-human TIMP-1 antibody (1.0 µg/ml; Oncogene Science, Cambridge, MA, USA) in 10% non-fat milk and Tris-buffered saline, containing 0.01% Tween-20. The membranes were subsequently washed with Tris-buffered saline, containing 0.5% Tween-20 and incubated for 1 h with horseradish peroxidase-conjugated rabbit anti-mouse immunoglobulins as the secondary antibody (1 µg/ml; Jackson ImmunoResearch, West Grove, PA, USA) in 10% non-fat milk and Tris-buffered saline, containing 0.01% Tween-20. The protein bands were then detected by enhanced chemiluminescence (Amersham International) and quantified by densitometry as above.
Statistical methods
Statistical analysis of the data was performed using Student's t-test when two treatments were compared and by analysis of variance when more than two incubation periods were evaluated (e.g. dose-dependent responses). P < 0.05 was considered significant.
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Results |
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Determination of optimum incubation time and relative compartmental abundance for MMP-9, MMP-2 and TIMP-1 production
For the purpose of scaling the assay methods to their optimum, we designed a pilot study to evaluate the lag time after which MMP-9, MMP-2 and TIMP-1 concentration in the medium will allow the best discriminative power for further experiments. In order to achieve this, we collected samples from four patients, and prepared the samples as described. The samples containing all three compartments as described above (amniotic membrane, decidua and chorion) were incubated for 24, 48, 72 or 96 h in HTF medium, without serum. A zymographic gel for MMP-2 and MMP-9 and a Western blot for TIMP-1 were prepared for all time points. The levels of gelatinases in the medium at the various time points are shown in Figure 1
. The activity of MMP-9 increased in all compartments during the interval between 24 and 72 h. The activity of MMP-2 did not change significantly from 24 to 96 h of incubation. It is notable that, relative to the amount of tissue, decidua produced significantly more (P < 0.05; n = 6 experiments) MMP-2 and MMP-9 than did chorion and amnion. As observed in the Western blot, the secretion of TIMP-1 increased from 24 to 72 h but not after that (Figure 2). Thus, the optimal time for further assays was 48–72 h. Here again, the secretion by the decidua was significantly higher compared to that by the fetal membranes (P < 0.05; n = 6 experiments).
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Effect of PGF2
on the production of MMP-2 and MMP-9 in decidua, chorion and amnionSamples of amniotic membrane, decidua and chorion obtained from six patients were incubated for 72 h in HTF medium in the absence or presence of PGF2
0.1, 1.0 or 10 µg/ml. As seen in Figure 3, incubation of decidua with PGF2 1.0 µg/ml caused a 2.4- and 1.9-fold increase in the production of MMP-2 and MMP-9 respectively, as compared to the control (P < 0.05). Moreover, this incubation increased by 11.3-fold the active form of MMP-2 (62 kDa), which could hardly be detected in basal culture conditions (P < 0.01). In a sharp contrast to the decidua, incubation of chorion and amnion tissue with PGF2 did not affect the production of MMP-2 and MMP-9.
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Effect of PGF2
on TIMP-1 production in decidua, chorion and amnionSamples of amniotic membrane, decidua and chorion from six patients were incubated for 72 h in HTF medium, without serum, in the absence or presence of PGF2
0.1, 1.0 or 10 µg/ml (Figure 4). As with the MMP, only decidual tissue was affected by the incubation with PGF2, which significantly decreased TIMP-1 production by 70% with 10 µg/ml (P < 0.05). Thus, the net gelatinolytic activity was markedly increased by PGF2.
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Effect of indomethacin on MMP-2 and MMP-9 production in decidua, chorion and amnion
Samples of amniotic membrane, decidua and chorion obtained from six patients were incubated for 72 h in HTF medium in the absence or presence of indomethacin 10–4, 10–5 or 10–6 mol/l. Incubation with indomethacin 10–4 mol/l decreased the activity of MMP-2 by 78% in chorion and by 70% in amnion (P < 0.05). The same concentration of indomethacin decreased MMP-9 35% in chorion and 58% in amnion (P < 0.05). In decidual tissue indomethacin had no effect on expression of either MMP (Figure 5
).
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Effect of indomethacin on TIMP-1 production in decidua, chorion and amnion
Samples of amniotic membrane, decidua and chorion obtained from six patients were incubated for 72 h in HTF medium in the absence or presence of indomethacin 10–4, 10–5 or 10–6 mol/l. Incubation with indomethacin 10–5 mol/l significantly increased the production of TIMP-1 by chorion (4.1-fold; P < 0.01). Indomethacin 10–4 mol/l also significantly increased TIMP-1 production by amnion (4.5-fold; P < 0.01) but none of the concentrations of indomethacin had any effect in this regard on decidual tissue (Figure 6
).
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Discussion |
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In this study of MMP and TIMP-1 production, we meticulously separated the three different compartments of the prelabour fetal–maternal interface, membranes taken at the edge of the placenta. This approach enabled us to analyse the relative contribution of each compartment to the general ability to produce collagenolytic activity, en route to the tissue disintegration during labour. This disintegration involves two main events, taking place at the initiation and propagation of labour. One is weakening of the membranes towards rupture and the other is further disintegration of the decidua, which provides additional phospholipases to the process of prostaglandin production. We found that before the onset of contractions, the decidua had the highest production of MMP-2 and MMP-9 and TIMP-1. We further demonstrated that the exposure to PGF2
greatly increased the production of MMP-9 and MMP-2 but decreased TIMP-1 production, resulting in a shift of the balance between collagenolysis and its inhibition. Vadillo-Ortega et al. (1995) have examined the levels of the same constituents in fetal membrane extracts (Vadillo-Ortega et al., 1995). They suggested that MMP-2, unlike MMP-9, is constitutively expressed in the membranes and its functional activation is by proteolytic cleavage. We did not measure the tissue levels, rather we measured MMP-2 levels that were secreted to the medium by the tissue. Reconciliation of these two apparently differing observations is possible if one assumes that activation and release from the cells and activation are two independent steps.
PG are known to be involved in the cascade of events leading to cervical softening, contractions and labour. The production of PGE2 and PGF2 by amnion and chorion have been shown to be more prominent in patients during spontaneous labour compared with that in patients undergoing elective Caesarean section (Brennand et al., 1998). Thus, the provision of PGF2 to the respective cultures could be considered as a stimulus that mimics the onset of labour.
The ability of PG to induce the production of MMP has been the subject of several studies. Exposure to PGF2 increases production of MMP-2 and MMP-9 in ciliary smooth muscle cells (Weinreb et al., 1997). PGE2 and PGE1 are potent stimulators of MMP-13 transcription, whereas PGI2 and PGF2 are weak stimulators (Clohisy et al., 1994). Zahner et al. have demonstrated that PGE2 stimulates the transcription, protein formation and enzymatic activity of MMP-2 in cultured rat mesangial cells (Zahner et al., 1997). However, before we initiated the study, we could not find any published work that directly documented this in fetal membranes and decidua. Interestingly enough, several cytokines have been shown to increase MMP-2 and MMP-9 production in these tissues (Osmers et al., 1995a,b; Watari et al., 1999). The same cytokines have also been shown to increase the production of PG (Khatun et al., 1999; Rauk and Chiao, 2000), but a cascade was not suggested.
In addition to the increase of collagenolytic activity by PGF2, we found that upon incubation with indomethacin, which is an established inhibitor of prostaglandin production and of labour, the expression of both MMP-2 and MMP-9 in the two fetal membranes was decreased. The production of TIMP-1 was at the same time increased in both fetal membranes. Decidual production of MMP and TIMP was unaffected by incubation with indomethacin. Taken together, these data suggest an overall effect of indomethacin that, by inhibiting PG production and also increasing the production of TIMP-1, protects the membranes from disintegration by MMP, originating in the adjacent decidua. Indomethacin has been shown in several studies to decrease the expression of both MMP-2 and MMP-9 and to increase the production of TIMP-1 (Mehindate et al., 1995; Yamada et al., 1996; Li et al., 1997; Miralles et al., 1999; Morin et al., 1999). A recent study (McLaren et al., 2000) addressed the same general question as we did, but only in fetal membranes and not decidua. They examined only MMP-9 and TIMP-1, and found that PGE2 increased production of MMP-9 and did not affect TIMP-1, and that indomethacin reversed this induction. Our findings, that indomethacin most significantly increases TIMP-1 production in the membranes, adds an additional aspect of regulation to their observations. Our overall findings, stemming from the separation of the three respective layers, indicates that this is true only in the membranes.
The decidua is known to produce phospholipases, which in turn lead to PG production from the arachidonic acid reservoir in the fetal membranes. Our findings, that PG increase the ability of the decidua to degrade its own ECM by increasing MMP 2 and MMP-9 and by reducing TIMP-1, delineates a putative positive feedback mechanism towards further decidual disintegration during labour. The labour-arresting effect of indomethacin seems to originate from its ability to further reduce MMP prodution by fetal membranes and, importantly, to increase TIMP-1 production to protect the membranes from further degradation by MMP of decidual origin.
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Notes |
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3 On leave from the Bahceci Women's Health Care Center, Istanbul, Turkey
4 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Ha'Emek Medical Centre, Afula 18101, Israel. E-mail: shalev_e{at}hotmail.com
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Submitted on April 9, 2001; accepted on August 17, 2001.
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 S. Goldman, A. Weiss, I. Almalah, and E. Shalev Progesterone receptor expression in human decidua and fetal membranes before and after contractions: possible mechanism for functional progesterone withdrawal Mol. Hum. Reprod., April 1, 2005; 11(4): 269 - 277. [Abstract] [Full Text] [PDF]
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 W. Li, N. Alfaidy, and J. R. G. Challis Expression of Extracellular Matrix Metalloproteinase Inducer in Human Placenta and Fetal Membranes at Term Labor J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2897 - 2904. [Abstract] [Full Text] [PDF]
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S. Goldman, A. Weiss, V. Eyali, and E. Shalev Differential activity of the gelatinases (matrix metalloproteinases 2 and 9) in the fetal membranes and decidua, associated with labour Mol. Hum. Reprod., June 1, 2003; 9(6): 367 - 373. [Abstract] [Full Text] [PDF]
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