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The Department of Obstetrics and Gynecology, New York University Medical Center, New York, New York 10016
Address all correspondence and requests for reprints to: Dr. Frederick Schatz, Department of Obstetrics and Gynecology, New York University Medical Center, 550 First Avenue, New York, New York 10016.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The matrix metalloproteinases (MMPs) degrade the bulk of ECM components during tissue remodeling. Based on substrate specificity, the MMPs are grouped into: 1) collagenases, which regulate interstitial ECM turnover by degrading interstitial collagens types I, II, and III via a specific cleavage that denatures the helical structure of these fibrillar collagens; 2) gelatinases, which degrade basement membrane collagens IV and V as well as denatured interstitial collagens (gelatins); and 3) stromelysins, which degrade such diverse ECM proteins as proteoglycans, glycoproteins, fibronectin, and laminin, and can cleave the globular domain of interstitial (type III) and basement membrane collagen type IV and V (6, 7, 8).
Previous studies showed that progestins inhibited, and E plus progestin markedly inhibited, stromelysin-1 (MMP-3) expression in monolayers of HESCs, whereas the cells were refractory to E added alone (9, 10). These responses mimic differential ovarian steroids effects on the induction of decidualization in vivo in which E primes the endometrium for the differentiating effects of progesterone by enhancing progesterone receptor levels (11, 12). Moreover, the progestin-inhibited expression of MMP-3 was reversed by steroid withdrawal (9). This response to removal of steroid stimulation suggests that in vitro decidualized HESCs constitute a relevant model for menstruation, which is initiated by steroid withdrawal. Thus, decidual cell-expressed MMP-3 would be expected to promote ECM degradation preceding sloughing of the functional layer.
Fibrillar collagens are key components of the endometrial ECM during trophoblast invasion and at the time of menstruation. Denaturation of these collagens by interstitial collagenase (MMP-1) is mandatory for further processing by stromelysins, such as MMP-3, and gelatinases, such as the 72-kDa gelatinase-A (MMP-2) (7, 8). The current study sought to determine whether MMP-1 and MMP-2 expression conformed to the pattern established for MMP-3 during progestin-regulated in vitro decidualization and after subjecting in vitro decidualized HESCs to steroid withdrawal. The in vitro measurements were extended to include the tissue inhibitor of matrix metalloproteinase (TIMP-1) to evaluate its potential role in regulating MMP activity. The effects of the antiprogestin-antiglucocorticoid RU 486 (mifepristone) were tested in the in vitro menstruation model because accelerated up-regulation in stromal/decidual cell MMP activity is consistent with enhanced endometrial ECM breakdown leading to the excess uterine bleeding that complicates the use of RU 486 as an abortifacient (13, 14).
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Materials and Methods |
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Experimental culture conditions
As previously described (16, 17), HESCs, isolated from two
specimens of proliferative phase tissue and ten specimens of early
secretory phase tissue, were grown to confluence (3–4 x
104 cells/cm2) in a 37 C, 95% air:5%
CO2 incubator in BMS, which consists of BM [a phenol
red-free 1:1 vol:vol mix of DMEM (Gibco BRL, Grand Island,
NY) and Ham’s F-12 (Flow Laboratories, Rockville, MD), with 100 U/ml
penicillin, 100 µg/ml streptomycin, 0.25 µg/ml fungizone]
supplemented with 10% charcoal-stripped calf serum (S).
Steroid specificity and time course
The experimental period was initiated in either fresh BMS, or in
a serum-free defined medium (DM) [BM + ITS+
(Collaborative Research, Waltham, MA), 5 µM
FeS04, 50 µM ZnSO4, 1
nM CuSO4, 20 nM
Na2SeO3, trace elements (Gibco), 50ug/ml
ascorbic acid (Sigma Chemical Co., St. Louis, MO), and 50
ng/ml EGF] containing steroids added alone or in combination, or 0.1%
ethanol as vehicle control. After 3–5 experimental days in the
incubator, the collected medium was centrifuged and the supernatants
stored at -70 C (see below). The cells of one set of dishes were
harvested, then centrifuged and frozen for later determination of
protein and DNA content. Fresh corresponding medium was added to the
remaining set(s) of cultures. These were returned to the incubator, and
the procedure was repeated for additional 3- to 5-day intervals.
Steroid withdrawal
Using the protocol outlined in Fig. 1
, confluent HESCs were incubated in BMS
containing 10-8 M-1 E and
10-7 M-1 medroxyprogesterone
acetate (P) in the 37 C incubator, replacing the medium every 3–5
days. After 10 days, the cultures were washed twice with BMS, and
steroid withdrawal was carried out for 4 days in BMS containing either
vehicle control, or 10-6 M-1 RU
486, while parallel cultures were maintained in 10-8
M-1 E plus 10-7
M-1 P. In some experiments the steroid
withdrawal protocol was modified by carrying out withdrawal; 1) for
additional 4- and 8-day intervals, or 2) in parallel in either BMS, or
in DM, or 3) with onapristone (Schering AG, Berlin,
Germany) substituted for RU 486, or 4) in medium containing E +
P + RU 486. The experiments were terminated as described above, storing
the centrifuged conditioned medium at -70 C, and harvesting the cells
for total protein and DNA measurements. Parallel cultures were washed
with HBSS and frozen at -70 C for Northern analysis.
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MMP-1 ELISA
Stromal cell conditioned medium was assayed for immunoreactive
MMP-1 levels by a specific ELISA according to the manufacturer’s
specifications (Oncogene Research Products, Inc.,
Cambridge, MA).
Protein and DNA assay
Protein and DNA content of the cell pellets was determined by a
modified Bradford assay (Bio-Rad Laboratories, Inc., Hercules,
CA), and by the method of Hinegardner (18),
respectively.
Northern analysis
Total RNA was extracted from cultured HESCs with RNAzol-B (Cinna
Biotecx Laboratories, Houston, TX). Approximately 25 µg total RNA
from each of the experimental cultures, and mol wt RNA standards
(Boehringer Mannheim, Indianapolis, IN) were separated on a 1% agarose
gel containing 2.2 M-1 formaldehyde, then
transferred to a Zeta-Probe nylon membrane (Bio-Rad
Laboratories, Inc.). Levels of MMP-1, MMP-2 and TIMP-1 messenger
RNA (mRNA) were detected with probes generously supplied by Dr. N.
Hutchinson (Merck & Co., Rahway, NJ), which were labeled
with [32P]deoxy-CTP to high specific activity by random
priming with a Boehringer Mannheim kit. Hybridization was performed by
standard methods as previously described (19), and the washed filters
were exposed to Kodak XAR film. (Eastman Kodak Co.,
Rochester, NY). Total RNA loads were standardized by reprobing the
stripped membranes with either 32P-labeled probes for
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (CLONTECH
Laboratories, Inc., Palo Alto, CA) (19), or cyclophylin
(20).
Statistical analysis
Statistical comparisons were made with the Mann-Whitney Rank Sum
Test with P < 0.05 considered significant.
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Results |
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compares
immunoreactive pro-MMP-1 levels in the conditioned medium of HESCs
incubated in parallel in BMS or DM supplemented with E, or
medroxyprogesterone acetate (P), or E + P. Secreted levels of
pro-MMP-1, were reduced in response to P but not to E, with greater
inhibition resulting from coincubation with E + P in BMS. While
progestin-mediated inhibition of pro-MMP-1 was evident in both media,
pro-MMP-1 output was considerably greater in BMS. The effects of E and
E + P were also studied on HESC-secreted levels of pro-MMP-1, during
incubation in BMS for three consecutive 4- to 5-day intervals (Fig. 3). Virtually complete inhibition was
evident by 14 days in response to E + P, which simulates the duration
of endometrial exposure to E and progesterone during the luteal
phase.
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confirms that P, but not E, inhibited steady state levels of MMP-1
mRNA. However, neither E nor P altered levels of MMP-2 or TIMP-1 mRNA
(Fig. 4).
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was used to compare the effects of steroid withdrawal on MMP-1,
MMP-2, and TIMP-1 mRNA levels with those previously established for
MMP-3 mRNA (26). Northern blot analysis (Fig. 5) shows that after suppressing both
MMP-1 and MMP-3 mRNA levels during 10 days of incubation with E + P, 8
days of steroid withdrawal to control BMS up-regulated steady state
levels of both mRNAs compared with parallel cultures maintained in E +
P. As expected, more effective up-regulation occurred when the
progesterone receptor antagonist RU 486 (14, 27, 28) was added alone or
with E + P to the culture medium. Unlike the changes seen for MMP-1 and
MMP-3 mRNA, levels of MMP-2 and TIMP-1 mRNA in the HESCs were
unaffected by steroid withdrawal to either control or to RU
486-containing medium.
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. The immunoblot of Fig. 6 shows that at the end of the 0–4 day
withdrawal interval, compared with cultures maintained in E + P,
secreted levels of pro-MMP-1 (about 50 kDa) were markedly increased
whether the medium was supplemented with RU 486 added alone or with E +
P. However, only marginal up-regulation resulted from withdrawal to
steroid-free control medium. During the subsequent 4–8 days of
withdrawal, the change to control medium was now nearly as effective as
RU 486 in increasing pro-MMP-1 levels (Fig. 6). The latter effect is
consistent with removal of residual steroid from the cultures during
the additional medium change and prolonged incubation of the second
withdrawal interval.
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. Figure 7A shows that
after the 0–4 day steroid withdrawal interval, secreted pro-MMP-1
levels were no different in parallel cultures of HESCs that were either
maintained in E + P or withdrawn to steroid-free medium (C), whereas RU
486 up-regulated pro-MMP-1 levels by about 5-fold (P <
0.05, n = 7). At the end of the 8- to 12-day withdrawal interval,
RU 486 elicited a further 2.5- to 3-fold increase in secreted MMP-1
levels. Furthermore, the switch to control medium up-regulated secreted
MMP-1 to levels that were nearly equivalent with that produced by RU
486. Although RU 486 is an antiprogestin that can also act as an
antiglucocorticoid at high concentrations (14), the purer
antiprogestin, onapristone (29), was as effective as RU 486 in
reversing the inhibitory effects of E + P on HESC-secreted MMP-1 levels
(results not shown). This observation further emphasizes the progestin
specificity of inhibited MMP-1 expression.
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shows immunogenic levels of pro-MMP-1 in the conditioned
medium of first passage HESCs that were subjected in parallel to
steroid withdrawal in either a serum-containing medium (BMS), or in
DM. In BMS, the pattern of secreted pro-MMP-1 was similar to that
displayed by primary HESCs (Fig. 7A). However, pro-MMP-1 levels were
much lower in the conditioned medium of first passage than of primary
HESCs (Fig. 7B). For example, the reversal in progestin-inhibited
pro-MMP-1 output elicited by RU 486 in primary HESCs (7A) was 30- to
80-fold greater than that elicited in the passaged HESCs during the
corresponding withdrawal interval (7B). Moreover, DM failed to support
pro-MMP-1 output by the passaged cells. Thus, 7B shows that secreted
levels of pro-MMP-1 were greatly reduced in incubations performed in DM
compared with BMS, with withdrawal effects attenuated by the end of the
4- to 8-day withdrawal interval (note the difference in ordinate scale
between 7A and 7B). |
Discussion |
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The simultaneous inhibition of MMP-1, MMP-3, and uPA expression in stromal/decidual cells in response to circulating levels of E and progesterone modulates the composition of the luteal phase and pregnant endometrial ECM. Following implantation, the endometrial ECM promotes trophoblast adhesion, migration and differentiation (33), yet prevents the trophoblast from penetrating into the myometrium (1). The gestational endometrial ECM also provides structural support for blood vessels, thereby counteracting the threat of local hemorrhage during endovascular trophoblast invasion (34). In nonfertile cycles, the decline in circulating levels of ovarian steroids stemming from regression of the corpus luteum, initiates menstruation.
The suitability of in vitro decidualized HESCs as a menstruation model was suggested from reports that steroid withdrawal reversed E + P-inhibited uPA activity (23) and pro-MMP-3 levels (26) in HESCs. The action of MMP-1 is required for fibrillar collagen degradation. Therefore, the demonstration in the current study that steroid withdrawal also reverses inhibited MMP-1 expression is a critical addition to the menstruation model because it accounts for degradation of residual interstitial collagens in the peri-decidual cell ECM. Extrapolation of the up-regulation in uPA, MMP-3, and MMP-1 expression by in vitro decidualized HESCs to decidual cells of the perimenstrual endometrium is consistent with ECM degradation leading to sloughing of the functional endometrial layer. The clinical use of RU 486 is complicated by pronounced endometrial ECM degradation and excessive menstrual bleeding (13, 14). The marked effectiveness of RU 486 in reversing the expression of progestin-inhibited uPA (23), and MMP-3 (26), and as shown in the current study, MMP-1, emphasizes the relevance of in vitro decidualized stromal cells in the screening of antiprogestins for potential menstruation-inducing activity.
In the current study, the profound changes in steady-state levels of
MMP-1 and MMP-3 mRNA observed during progestin-mediated decidualization
and in decidualized HESCs subjected to steroid withdrawal contrast
sharply with the lack of effect on MMP-2 mRNA levels. However, Irwin
et al. (35) reported that steroid withdrawal markedly
up-regulated MMP-2 expression in cultured HESCs. The explanation for
these contradictory results likely lies in differences in the culturing
conditions used in the two studies. Thus, Irwin et al. (35)
apparently used HESCs obtained after multiple passages that were
cultured in a serum-free medium. However, Fig. 7B shows that MMP-1
secretion is markedly reduced after one passage, and that steroid
withdrawal effects were much greater in BMS than in DM.
The importance of validating alterations in MMP expression in cultured cells with parallel measurements in vivo is well documented (31, 36). Toward that end, Rodgers et al. (37) meticulously localized MMP and TIMP mRNA levels to the stromal and epithelial compartments of specimens of cycling human endometrium by in situ hybridization. Their observations support the results of the current study. They demonstrated that MMP-3 mRNA was strongly expressed and MMP-1 mRNA was weakly expressed in the stroma of follicular phase endometrium. Both mRNA species were reduced to nondetectable levels during the progesterone-dominated luteal phase, then up-regulated in correspondence with steroid withdrawal leading to menstruation (37). By contrast, MMP-2 and TIMP-1 mRNA were maintained at constant levels in the stromal compartment throughout most of the menstrual cycle, with only marginal up-regulation evident in the peri-menstrual period (37). Marbaix et al. (38) provided in vitro support for progestational inhibition of MMP-1 expression in human endometrium by observing that MMP-1 mRNA, protein, and activity were measurable only in explants obtained from the progestin-withdrawal initiated peri-menstrual phase.
Coordinate changes in the expression of the MMP-1 and MMP-3 genes have been attributed to similarities in their promoter regions. These contain 1) a TATA box; 2) at least one AP-1 site, which binds c-fos/c-jun heterodimers; and 3) at least one PEA-3 site, an oncogene response element that responds to the c-ets family of transcription factors. In several cell systems, the combination of AP-1 and PEA-3 sites mediates growth factor and oncogene induction of MMP-1 and MMP-3 gene expression, whereas the corticosteroid-receptor complex can interfere with AP-1-enhanced MMP-1 expression. By contrast, the MMP-2 promoter is devoid of such response elements [see review by Matrisian (31)]. As expected from the constitutive nature of its promoter, MMP-2 expression is insensitive to exogenous growth factors, cytokines, hormones, and neural cell-adhesion molecules (NCAMs) in several cell types (31, 39). Unlike the MMP-2 promoter, that of the other member of the gelatinase subclass, the 92-kDa gelatinase-B (MMP-9), contains similar response elements to those found on the MMP-1 and MMP-3 promoters. Predictably, cultured HESCs responded to interleukin 1, tumor necrosis factor, and phorbol myristate acetate with enhanced MMP-1, MMP-3, and MMP-9 gene expression, whereas the MMP-2 gene was unresponsive (40).
Previous studies described PAI-1 as the primary regulator of progestin-inhibited uPA catalytic activity during both in vitro decidualization of HESCs as well as its subsequent up regulation in response to steroid withdrawal (22, 23). By contrast, the current study shows that the profound changes in MMP-1 and MMP-3 expression that occur during in vitro decidualization, and after subjecting in vitro decidualized HESCs to steroid withdrawal, were accompanied by unchanging levels of TIMP-1 mRNA. A recent report in which cultured HESCs were primed with a progestin alone extended the absence of a progestin withdrawal effect on HESC-expressed MMP inhibitors to include TIMP-2 and TIMP-3 (41). Thus, progesterone regulation of HESC/decidual cell-expressed uPA, which promotes degradation of provisional ECM components, occurs secondary to changes in the expression of the PAI-1 inhibitor, whereas the genes for MMP-1 and MMP-3, which promote breakdown of the structural components of the endometrial ECM, are controlled by progesterone without TIMP intervention. Cytokines and growth factors derived from decidual cells, endothelial cells and leukocytes are likely to modulate decidual-expressed proteases during menstruation with trophoblasts serving as an additional source of paracrine effectors during implantation (42). Identification of autocrine/paracrine agents that interact with ovarian steroids to differentially regulate expression of uPA and MMPs by endometrial stromal/decidual cells presents a major challenge in reproductive biology.
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Footnotes |
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Received December 2, 1997.
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