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Reproductive Endocrinology |
Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Dr. L. A. Salamonsen, Prince Henry’s Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia. E-mail: \|[lt ]\|lois.salamonsen{at}med.monash.edu.au\|[gt ]\|
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Matrix metalloproteinases (MMPs) are the family of enzymes that degrade
components of both interstitial and basement membrane extracellular
matrix: different members of the family have different substrate
specificities, although there is considerable overlap (4). Importantly,
the MMPs are active at the neutral pH of the extracellular space, and
all are secreted in their latent forms, which require activation.
In vitro, this can be achieved by a number of natural
proteases, including MMP-3 (stromelysin 1), MMP-7 (matrilysin), and the
membrane-type MMPs or by treatment with organomercurial compounds. Each
MMP can be inhibited by specific inhibitors of MMPs (TIMPs) by the
formation of 1:1 complexes or, less specifically, by 
2
macroglobulin. The genes for MMPs and TIMPs are regulated by a number
of biologically active factors, including steroid hormones
(glucocorticoids and progesterone), growth factors, and cytokines, with
considerable variation between tissues, cell types, and MMPs (5).
There is now substantial evidence that MMPs are produced in the endometrium and that expression of their messenger RNA (mRNA) is closely correlated with the process of normal menstruation (6, 7, 8, 9, 10); how this expression is regulated is not well understood (11). It has been demonstrated that progesterone withdrawal modulates the production of proMMP-1 (interstitial collagenase) by explants of both proliferative and secretory-phase endometrial tissue but not by those taken close to the time of menstruation (7). Likewise, progesterone withdrawal increases production of proMMP-2 [gelatinase A (12)] and proMMP-3 (13) by decidualized stromal cells in culture. Whether TIMP production also is affected in such systems has not been examined. The balance between the MMPs and their natural inhibitors is of primary importance in determining whether tissue degradation will occur at any given site. The present study was therefore undertaken to examine the effect of P withdrawal on the full complement of MMPs and TIMPs (and thus, the MMP:TIMP balance) secreted from primary cultures of decidualized endometrial stromal cells, using conditions designed to mimic the late luteal phase of the menstrual cycle.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Endometrial tissue was obtained, by curettage, from consenting women being assessed for tubal patency and with no evidence of endometrial dysfunction. Tissue dating was initially from the patient’s testimony and was confirmed histologically. Perimenstrual and menstrual tissues were specifically excluded from the study: all tissues used were from between cycle days 8–24. Protocols were approved by institutional human ethics committees.
Cell isolation and culture
Stromal cells were prepared from human endometrial tissue, as described previously (14). Briefly, chopped tissue was digested with bacterial collagenase type III (Worthington Biochemical Corporation, Freehold, NJ), at a concentration of 45U/mL, in the presence of 3.5 µg/mL deoxyribonuclease (Boehringer Mannheim Biochemica, Mannheim, Germany) for 40 min at 37 C, filtered sequentially through 45- and 10-µm nylon filters to remove glands, and erythrocytes removed by centrifugation on Ficoll-Paque (Pharmacia, Uppsala, Sweden). Epithelial glands were recovered from the filters by backwashing (15). The resulting cells or glands were resuspended in a 1:1 mixture of DMEM and Ham’s F12 medium (Trace Biosciences, Sydney, Australia) with 10% charcoal-stripped FCS and antibiotics (penicillin, streptomycin, and fungizone) and plated in 24-well dishes (2 x 105 stromal cells or 1000 glands per well) or at a similar density in flasks for subsequent RNA preparation. After 48 h, when the cells were nearly confluent, they were washed, and medium was replaced with serum-free medium containing: insulin (10 µg/mL; human Actrapid, Novo-Nordisk Pharmaceuticals Pty. Ltd., Sydney, Australia); transferrin (10 µg/mL; Sigma Chemical Company, St. Louis, MO); sodium selenite (25 ng/mL; Sigma); epidermal growth factor (50 ng/mL; Sigma); linoleic acid (10 nmol/L; Sigma); and BSA (0.1%; Sigma). Estradiol 17ß (E, 10 nmol/L; Sigma) also was added with or without the synthetic progestin ORG2058 (P: 100 nmol/L; Organon Laboratories Ltd.), chosen for its stability in culture systems compared with natural progesterone (16). For the stromal vs.. epithelial cell analyses, medium was harvested 48 h after the change to serum-free conditions (day 2). Otherwise, cultures were maintained thus for 6 days, with changes of medium every 48 h. For the P withdrawal experiments, the cells were washed on day 6 and medium replaced either with (control) or without P. All experiments were performed in triplicate or quadruplicate wells. Cultures were terminated on day 10. Medium was centrifuged and stored at -20 C. Cells were taken for DNA analysis or for RNA preparation. Cells for immunohistochemistry were grown on serum-coated glass cover slips.
DNA assay
The DNA content of wells was determined fluorometrically (17).
Zymography and reverse zymography
Proteinase activity in unconcentrated medium samples was analyzed by zymography on 10% SDS-polyacrylamide gels containing 1 mg/mL gelatin (all reagents from BioRad, North Ryde, Australia) or 1 mg/mL casein (Sigma) under nonreducing conditions (14). Loading of samples was normalized according to the DNA content of wells. Gelatinase or caseinase activity was visualized by negative staining, and bands were identified by comparison with pure human MMPs (a gift from Dr. Hideaki Nagase, Kansas City, KS) and with molecular weight markers (BioRad; (14)). MMP identity of bands was confirmed by incubation of parallel gels in the presence of ethylenediamine tetra-acetate (EDTA) or o-phenanthroline. Reverse zymography also was performed on unconcentrated culture medium using gels of 12% polyacrylamide containing 1% gelatin and an MMP preparation from BHK-21 cells that constitutively express proMMP-2 (18). The presence of TIMPs was visualized by the presence of dark blue bands on a cleared background. Controls were standards containing mouse TIMP-1, -2, or -3, obtained from transfected BHK cells (provided by Dr. Dylan Edwards, Calgary, Canada), ovine luteal cell-conditioned medium containing TIMP-1 and -2 (a gift from Dr. Michael Smith, MO), and ovine endometrial cell conditioned medium, as previously described (18). Relative activities of MMPs or relative concentrations of TIMPs were semiquantitated by densitometric analysis of zymograms (19) using the Hewlett-Packard Scanjet IIp with Deskscan software (Hewlett-Packard, Palo Alto, CA) and area of the bands analyzed using the NIH Image Version 1.54 equipped with gel-plotting macros by measuring the area beneath the peaks plotted through the lane profile. Comparisons were made only between samples on the same gel. Analyses of doubling dilutions of samples on each of the three types of zymograms verified the semiquantitative nature of such analyses.
MMP-1 assay
MMP-1 was measured in culture medium by an enzyme-linked immunosorbent assay (ELISA) (Amersham Australia, Baulkham Hills, NSW), which detects total MMP-1 (proMMP-1, active MMP-1, and MMP-1/TIMP complexes).
Immunocytochemistry
Cells grown on glass cover slips were subjected to immunocytochemistry for PRL (a marker of decidual cells) using a rabbit polyclonal antibody against human pituitary PRL (National Institutes of Health, Bethesda, MD). Cells were fixed with 70% ethanol, treated with 0.1% trypsin (Sigma), washed, and further treated with hydrogen peroxide (0.6%) to block endogenous peroxide. Primary antiserum was used at 1:500, incubated overnight at 4 C, followed by goat antirabbit antiserum (Vector Laboratories, Burlinghame, CA) at 1:100 for 1h at room temperature. Development used the Vectastain ABC kit (Vector Laboratories), and nuclei were counterstained with Harris hematoxylin (1:10). Sections from human placenta and from late secretory phase human endometrium were used as positive controls.
Northern blot analysis
Complementary DNA (cDNA) probes against ovine TIMP-1 (900 bp)
and TIMP-2 (438 bp), both donated by Dr. M. Smith, Columbia, MO, were
labelled with 32P-deoxycytidine 5'-triphosphate
(Bresatec, Adelaide, Australia) to SA of 1–3 x 109
cpm/µg. A rat glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
complementary RNA probe, complementary to nucleotides 96–660 of the
rat GAPDH cDNA clone, was labeled with 32P-UTP to an SA
of 108 cpm/µg.
Total RNA was isolated from human endometrial cells using guanidinium isothiocyanate lysis and centrifugation through cesium chloride (20). For Northern blotting, 25 µg total RNA was denatured in 1 mol/L glyoxal with 50% dimethyl sulfoxide, electrophoresed in a 1.2% agarose gel, transferred to Hybond nylon membranes (Amersham International, Sydney, Australia), baked at 80 C for 2 h, UV cross-linked for 10 min, and prehybridized for 3 h in hybridization buffer [1 mmol/L EDTA, 0.5 mol/L sodium hydrogen phosphate (pH 7.2), and 7% SDS] at 65 C. Blots were hybridized with the appropriate 32P-labeled TIMP probe (1 x 106 cpm/mL) for 16 h at 65 C, washed at room temperature in buffer containing 2 x SSC with 0.1% SDS (1 x SSC is 0.15 mol/L sodium chloride and 15 mmol/L sodium citrate, pH 7.0) and in 0.5 x SSC, 0.1% SDS at 70 C for the TIMP-1 probe and at 1 x SSC, 0.1% SDS at 55 C for the TIMP-2 probe. Autoradiography used Fuji RX film (Fuji, Tokyo, Japan) and an intensifying screen at -80 C for 3 days and 1 day, respectively. For the GAPDH probe (1 x 106 cpm/mL), prehybridization was for 3 h at 65 C in hybridization buffer [50% formamide, 5 x SSPE (1 x SSPE is 0.15 mol/L sodium chloride, 10 mmol/L sodium phosphate, and 1 mmol/L EDTA, pH 8.0)], 0.15 mol/L tris(hydroxymethyl)aminomethane [Tris]-HCl (pH 8.0), 1% SDS, and 500 µg/mL heparin sodium. Hybridization was for 16 h at 65 C, and the blot was washed, initially in 2 x SSC and 0.1% SDS at room temperature and then in 0.1 x SSC and 0.1% SDS at 50 C. Autoradiography was for 5 days. Densitometric analysis of autoradiographs was performed using the Hewlett-Packard Scanjet IIp, as above. Data are expressed as relative densitometric units, corrected for loading according to the relative intensity of hybridization of the GAPDH probe.
Statistical analysis
All data are given as mean ± SEM. Combined data from 3 or 4 separate experiments for the two treatment groups, or from quadruplicate wells within an experiment for the two treatment groups, were analyzed by paired Student’s t test. Differences were considered significant at the 0.05 level.
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Results |
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Zymographic analyses demonstrated that all endometrial stromal
cell cultures, collected on both 2 and 10 days after change to
serum-free conditions, released MMPs-1, -2, -3, and -9 into culture
medium, although there was quantitative variability between cell
preparations derived from different individuals. The relative patterns
of MMP production from each batch of cells were similar, with
substantially more proMMP-2 than proMMP-9 and more proMMP-1 than
proMMP-3 in the culture medium. The MMPs were identified by comparison
of their molecular weights with standard proMMPs and by inhibition of
their activities with EDTA or o-phenanthroline (14). When the medium
was harvested at 2 days from separate pairs of stromal and epithelial
cultures from three women and analyzed by zymography, in every case,
the quantity of each MMP was substantially greater from stromal than
from endometrial cells; the combined data, after semiquantitation of
the zymograms by densitometry, is shown in Fig. 1
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Time course of MMP and TIMP production by decidualizing stromal cells
After 10 days of serum-free culture in the presence of E and P,
stromal cells stained positively for PRL, compared with negative
staining for the same batch of cells harvested on day 2 of culture
(Fig. 2), confirming that decidualization of the cells
occurred within this time. TIMPs -1, -2, and -3 increased steadily in
the culture medium with time in culture (Fig. 3). In
three of four cultures and at all times, there was substantially more
TIMP-1 in the culture medium than TIMP-2 or -3. Latent MMPs (-1, -2,
-3, and -9) also were released into the culture medium throughout the
10 days of culture, but there was a greater range of MMP-1, -3, and -9
activities, detected by zymography, between individual cell
preparations or days of culture (data not shown) than seen for the
TIMPs. ProMMP-2 was produced at a fairly constant level throughout the
period of culture at concentrations somewhat higher than those of
proMMP-9. ProMMP-3, although always present, was not always measurable
by densitometry.
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Image analysis of gelatin and casein zymograms
demonstrated that production of all four MMPs (MMP-1, -2, -3, and -9)
was increased 4 days after withdrawal of P from the cell cultures,
compared with the same day of control cultures in which P was retained
for the full 10 days of culture (Fig. 4). In all cases,
most of the MMP was present in its latent form. Assay of total MMP-1
(active, latent, and TIMP-bound) in the culture medium by ELISA
confirmed and emphasized the increased production after P withdrawal
(Fig. 5). No differences were observed between the
viability or metabolic activity of the cells in the two treatment
groups, as assessed by phase contrast microscopy, by uptake of trypan
blue and by the rate of change of color of the phenol red in the medium
(a good indicator of metabolic activity of such cells).
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). Likewise, there
was no alteration in the ratios of TIMP-1:TIMP-2:TIMP-3 in the media
whether P was retained or withdrawn, although there were differences in
the relative amounts of the three antigelatinases in medium from cell
cultures derived from different endometrial samples (Table 1). For example, the ratio between TIMP-1 and -2 varied
between 0.6:1 and 10:1. However, overall there was substantially more
TIMP-1 present in the culture medium than TIMP-3 or -2.
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When mRNA derived from decidualized stromal cells that had been
subjected either to continuous P for 10 days or P withdrawal from days
6–10 of culture was analyzed by Northern analysis, cDNA probes for
TIMP-1 and -2 hybridized to mRNA from both treatment groups (Fig. 7) with signals at 0.9 kb and 1.0 kb, respectively.
After densitometric analysis and correction for loading using relative
hybridization to a probe for GAPDH, no differences could be seen
between the two treatment groups.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cell culture model was designed to mimic some of the events of the latter part of the menstrual cycle, namely, the decidualization of endometrial stromal cells and their response to the withdrawal of P, with respect to the release of MMPs and TIMPs. Positive immunostaining for PRL, an early product of such cells in vivo (21), confirmed that the cells had decidualized in culture. Although the production of all four MMP products of these cells (proMMP-1, proMMP-2, proMMP-3, and proMMP-9) increased after withdrawal of P, no parallel effect was seen on the production of TIMP-1, -2, or -3 mRNA or protein. Thus, progesterone withdrawal from the endometrium has the potential both to increase the level of MMPs within the tissue and also to change the balance between the MMPs and TIMPs that would be required for active tissue degradation. These data support the growing body of evidence that implicates the MMPs in the process of menstruation, including our demonstration that mRNA for proMMP-1 and-3 is detectable by Northern analysis only during the perimenstrual and menstrual phases in endometrial tissue taken across the normal menstrual cycle (10). This follows the fall in circulating progesterone levels during the late luteal phase. mRNA for TIMP-1 and -2 also was increased in menstrual tissue at menstruation; the lack of responsiveness of TIMP-1, -2, and -3 production by cultured decidualized stromal cells, in response to withdrawal of progesterone, suggests that the increased expression of TIMP mRNA detected by Northern analysis may represent synthesis by other cell types in the functionalis endometrium or a paracrine action of their products on the stromal cells. The suggestion that TIMP-3 may be an early marker of decidualization (22) is confirmed by its production from the decidualized cells in this study.
Most MMPs were produced by endometrial stromal, but not epithelial cells in culture, supporting in situ hybridization and immunohistochemical studies in menstrual endometrium, showing mRNA for most MMPs and protein for MMP-1 and -3 in stromal cells. Matrilysin is the exception (8), and during the present studies, it was detected in culture medium from endometrial epithelial, but not stromal cells. TIMPs also were released primarily from stromal cells. MMP-9 is not detected in stromal cells in menstrual endometrium in vivo; immunolocalization confines it to migratory cells, including macrophages, eosinophils, and neutrophils (23). MMP-9 production occurs during culture of fibroblasts from a number of sources and is probably a property of cell culture, perhaps reflecting a state of recovery from injury or a lack of regulation via the extracellular matrix, which may occur in vivo.
The regulation of production of all four MMPs from endometrial stromal cells by P supports previous individual findings for proMMP-2 and -3 (12, 13). Inhibitory effects of P on proMMP-1 and -3 have been demonstrated in both uterine and cervical tissues (7, 24, 25). The promoters of the genes for these enzymes have sequences resembling steroid hormone response elements, along with AP-1 sites (see 26). However, the repression of the expression of proMMP-2 in decidualized endometrial stromal cells by progesterone is surprising, given the very different promoter regions in the proMMP-2 gene, which contains neither hormone response elements nor AP-1 sites (27).
Both TIMP-1 and -2 expression are increased by progesterone in rabbit cervical fibroblasts (25, 28), the increase in protein being greater than that of the mRNA, suggesting that translation or stability of the mRNA is affected. Although TIMP-3 is a product of human and rat decidual cells (22, 29), whether progesterone is directly responsible for regulation of TIMP-3 production or acts via its effect on decidualization is not known. In the present study, there was no effect of P withdrawal on TIMP-1, -2, or -3 protein or mRNA for TIMP-1 or -2 in decidualized endometrial stromal cells.
Many of the MMPs were partially activated in culture medium from menstrual endometrial explants (7), and steroid hormones seemed, at least partially responsible. In the present study, MMPs were primarily in their latent form, suggesting that activation probably requires contributions from other cell types. In addition to stromal fibroblasts and decidualized cells, endometrial stroma contains vascular elements and a variable population of inflammatory cells. In particular, menstrual endometrium contains activated mast cells and eosinophils (33), which probably contribute to the production of activators of latent MMPs. Mast cell tryptase is one potentially important activator, and its ability to activate proMMP-3 has the potential to set up a cascade of proMMP activation within the endometrium (30). Further, matrilysin, a product of endometrial epithelial cells during the perimenstrual and menstrual phases (8), has a similar ability to contribute to an activation cascade (31).
In vivo, MMPs are located in the functionalis layer of the endometrium at menstruation, particularly at foci undergoing fragmentation and lysis (11). Such focal action of MMPs implies that progesterone withdrawal per se cannot be solely responsible for their regulation. Indeed, it could be postulated that during the luteal phase of the cycle, progesterone functions, in part, to maintain MMP expression in a state of repression and that this is lifted as the levels of progesterone fall during the late secretory phase, permitting a basal production of MMPs that can be further stimulated at focal points by locally-acting regulators, such as cytokines (14, 32), derived both from epithelial cells and from the inflammatory cells that become activated in the endometrium at this time (33). The clearly multifactorial regulation of MMP activities at menstruation may explain, at least in part, the multiple etiologies of menorrhagia and other disorders of menstruation.
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Acknowledgments |
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Footnotes |
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Received August 27, 1996.
Revised December 18, 1996.
Accepted January 30, 1997.
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and tumor necrosis factor ß. J
Clin Endocrinol Metab. 79:530–536.[Abstract]
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T. E. Curry Jr and K. G. Osteen Cyclic Changes in the Matrix Metalloproteinase System in the Ovary and Uterus Biol Reprod, May 1, 2001; 64(5): 1285 - 1296. [Abstract] [Full Text]
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M. Nakano, T. Hara, T. Hayama, M. Obara, K. Yoshizato, and K. Ohama Membrane-type 1 matrix metalloproteinase is induced in decidual stroma without direct invasion by trophoblasts Mol. Hum. Reprod., March 1, 2001; 7(3): 271 - 277. [Abstract] [Full Text] [PDF]
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R.L. Jones, L.A. Salamonsen, H.O.D. Critchley, P.A.W. Rogers, B. Affandi, and J.K. Findlay Inhibin and activin subunits are differentially expressed in endometrial cells and leukocytes during the menstrual cycle, in early pregnancy and in women using progestin-only contraception Mol. Hum. Reprod., December 1, 2000; 6(12): 1107 - 1117. [Abstract] [Full Text] [PDF]
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L. J. Lathbury and L. A. Salamonsen In-vitro studies of the potential role of neutrophils in the process of menstruation Mol. Hum. Reprod., October 1, 2000; 6(10): 899 - 906. [Abstract] [Full Text] [PDF]
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N. R. Keller, E. Sierra-Rivera, E. Eisenberg, and K. G. Osteen Progesterone Exposure Prevents Matrix Metalloproteinase-3 (MMP-3) Stimulation by Interleukin-1{alpha} in Human Endometrial Stromal Cells J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1611 - 1619. [Abstract] [Full Text]
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J. Zhang, A. L. Hampton, G. Nie, and L. A. Salamonsen Progesterone Inhibits Activation of Latent Matrix Metalloproteinase (MMP)-2 by Membrane-Type 1 MMP: Enzymes Coordinately Expressed in Human Endometrium Biol Reprod, January 1, 2000; 62(1): 85 - 94. [Abstract] [Full Text]
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K. Liu, J. I. Olofsson, P. Wahlberg, and T. Ny Distinct Expression of Gelatinase A [Matrix Metalloproteinase (MMP)-2], Collagenase-3 (MMP-13), Membrane Type MMP 1 (MMP-14), and Tissue Inhibitor of MMPs Type 1 Mediated by Physiological Signals During Formation and Regression of the Rat Corpus Luteum Endocrinology, November 1, 1999; 140(11): 5330 - 5338. [Abstract] [Full Text]
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S. Freitas, G. Meduri, E. Le Nestour, P. Bausero, and M. Perrot-Applanat Expression of Metalloproteinases and Their Inhibitors in Blood Vesselsin Human Endometrium Biol Reprod, October 1, 1999; 61(4): 1070 - 1082. [Abstract] [Full Text]
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A.L. Hampton, G. Nie, and L.A. Salamonsen Progesterone analogues similarly modulate endometrial matrix metalloproteinase-1 and matrix metalloproteinase-3 and their inhibitor in a model for long-term contraceptive effects Mol. Hum. Reprod., April 1, 1999; 5(4): 365 - 371. [Abstract] [Full Text] [PDF]
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J. L. Skinner, S. C. Riley, A. E. Gebbie, A. F. Glasier, and H. O.D. Critchley Regulation of matrix metalloproteinase-9 in endometrium during the menstrual cycle and following administration of intrauterine levonorgestrel Hum. Reprod., March 1, 1999; 14(3): 793 - 799. [Abstract] [Full Text] [PDF]
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L. A. Rudolph-Owen, O. D. Slayden, L. M. Matrisian, and R. M. Brenner Matrix Metalloproteinase Expression in Macaca mulatta Endometrium: Evidence for Zone-Specific Regulatory Tissue Gradients Biol Reprod, December 1, 1998; 59(6): 1349 - 1359. [Abstract] [Full Text]
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C. J. Lockwood, G. Krikun, V. A. Hausknecht, C. Papp, and F. Schatz Matrix Metalloproteinase and Matrix Metalloproteinase Inhibitor Expression in Endometrial Stromal Cells during Progestin-Initiated Decidualization and Menstruation-Related Progestin Withdrawal Endocrinology, November 1, 1998; 139(11): 4607 - 4613. [Abstract] [Full Text] [PDF]
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G. T. C. Chen, S. Getsios, and C. D. MacCalman 17{beta}-Estradiol Potentiates the Stimulatory Effects of Progesterone on Cadherin-11 Expression in Cultured Human Endometrial Stromal Cells Endocrinology, August 1, 1998; 139(8): 3512 - 3519. [Abstract] [Full Text] [PDF]
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J. Zhang, G. Nie, W. Jian, D. E. Woolley, and L. A. Salamonsen Mast Cell Regulation of Human Endometrial Matrix Metalloproteinases: A Mechanism Underlying Menstruation Biol Reprod, July 1, 1998; 59(3): 693 - 703. [Abstract] [Full Text]
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)
and stromal (
) cells in culture. Medium was collected from confluent
cells on day 2 of culture and run on gelatin (MMP-2 and -9) or casein
(MMP-1 and -3) zymograms. Data are presented as mean relative
densitometric units ± SEM for each MMP and for
combined data from three cell preparations. *, P <
0.05, stromal vs. epithelial.
), TIMP-1; (•), TIMP-2; (
), TIMP-3. Data shown are
representative of one of three experiments.
) are expressed as a percentage
of those for mRNA from cells treated with continuous P (