Molecular Human Reproduction, Vol. 7, No. 6, 559-565,
June 2001
© 2001 European Society of Human Reproduction and Embryology
Uterine physiology |
Co-localization of matrix metalloproteinase-1 and mast cell tryptase in the human uterus
Obstetrics and Gynaecology Section, Department of Reproductive and Developmental Sciences, Centre for Reproductive Biology, University of Edinburgh, Edinburgh, UK
Abstract
The endometrium displays characteristic cyclical changes involving proliferation and differentiation. The differentiation that takes place requires major tissue remodelling involving the matrix metalloproteinase (MMP) family as key enzymes in this process. Mast cells, containing the tryptase and chymase enzymes that are capable of stimulating the MMP cascade, have been identified in the endometrium, but their role is still unclear. In this study, we observed that the majority of mast cells in the uterus reside in the myometrium and that they co-express mast cell tryptase and MMP-1 in the same intracellular granules. In endometrium exposed to synthetic progestogen via an intrauterine levonorgestrel system a significant increase in mast cells numbers was observed in women experiencing breakthrough bleeding compared to those in women with no reported bleeding. We conclude that mast cells contain MMP-1 and we postulate a potential role for mast cells in breakthrough bleeding.
endometrium/levonorgestrel-IUS mast cells/matrix metalloproteinase/myometrium/uterus
Introduction
Extensive and complex tissue breakdown and remodelling occurs in the endometrium at menstruation and during the menstrual cycle in preparation for a potential implantation. Matrix metalloproteinases (MMP) are an important family of enzymes involved in the breakdown of extracellular matrix and tissue remodelling (Salamonsen et al., 1997
).
The MMP family is divided into four enzyme groups: collagenases, stromelysins, gelatinases and membrane-bound types with a broad range of extracellular matrix substrates (Woessner, 1994; Nagase and Woessner, 1999). MMP-1 (interstitial collagenase), MMP-3, -10 and -11 (stromelysin 1, 2 and 3), MMP-2 and -9 (gelatinases A and B) and MMP-7 (matrilysin) are expressed and regulated at different stages of the menstrual cycle (Rodgers et al., 1994; Jeziorska et al., 1996). MMP-1, -3 and -9 are associated with degraded tissue (Salamonsen and Woolley, 1996) with down-regulation of MMP-1 being caused by progestins (Hampton et al., 1999) and up-regulation of MMP-1, -2 and -3 in endometrial stromal cells occurring after progestogen withdrawal (Salamonsen et al., 1997). Additionally, MMP-9 is regulated by progesterone in vivo (Skinner et al., 1999).
In endometrium, the major structural matrix is the fibrillar collagens. The family member MMP-1 is specific for these fibrillar collagens and is expressed in the endometrium where it is thought to play a key role in the breakdown of extracellular matrix during menstruation (Hampton and Salamonsen, 1994). MMP-1 sites of secretion have been identified using in-situ hybridization showing that MMP-1 mRNA is present in either superficial stromal cells or cells throughout the entire functional layer (Kokorine et al., 1996). Furthermore, the same authors found an excellent correlation between MMP-1 expression and tissue breakdown.
Human mast cells are haematopoietic cells characterized on their content of specific neutral protease and contain either tryptase alone (T-MC) or tryptase and chymase (TC-MC) (Irani et al., 1986; Irani and Schwartz, 1989). They have been identified in endometrium in small numbers, predominantly in the stromal tissue (Crow et al., 1991; Drudy et al., 1991). However, the greatest numbers of mast cells are in the myometrium (Rudolph et al., 1993; Roby and Hunt, 1995). Immunohistochemical studies in the myometrium have identified predominately T-MC in the functionalis and equal proportions of T-MC and TC-MC in the myometrium (Mori et al., 1997). Mast cell distribution and numbers are not altered throughout the menstrual cycle but they are activated prior to menses and ovulation when a diffuse staining pattern of immunoreactivity is observed (Jeziorska et al., 1995). Furthermore, in-vitro experiments have suggested a role for mast cells in the up-regulation of MMP prior to menses (Zhang et al., 1998).
Progestogen-only contraception is often associated with breakthrough bleeding and this side-effect is the commonest reason for discontinuation of this contraception method. The aetiology of breakthrough bleeding is not well understood and is likely to be multifactorial. The levonorgestrel-releasing intrauterine system (LNG-IUS; Leiras Oy, Turku, Finland) has been shown to reduce menstrual blood loss by 96% after 12 months use and hypomenorrhoea or amenorrhoea results in up to 65% of women (Andersson and Rybo, 1990). However, the occurrence of unpredictable breakthrough bleeding which can occur in up to 53% of women after 3 months use, leads to a high rate of discontinuation (Irvine et al., 1998). Studies on endometrium from women using LNG-IUS provide an opportunity to study the consequences of high dose local progestogen delivery on the endometrium and to examine normal regulation of uterine function.
In these studies, we have examined full thickness (superficial endometrium, the basalis-myometrial junction and myometrium) uterine biopsies to determine the temporal and spatial localization of mast cells and MMP-1 throughout the menstrual cycle. Furthermore, using an in-vivo model of progesterone withdrawal simulating luteal regression (Critchley et al., 1999), the role of progesterone on MMP-1 protein expression and mast cell traffic has been examined. Finally, the presence of mast cells and expression of MMP-1 in breakthrough bleeding was examined in biopsies from women using LNG-IUS.
Materials and methods
Subjects and source of endometrial tissue
Endometrial biopsies were available from four groups of subjects.
Full thickness, endometrial biopsies were obtained from women undergoing hysterectomy for a benign gynaecological indication (n = 12). All subjects reported regular menstrual cycles (cycle length 25–35 days) and no women had received a hormonal preparation in the 3 months preceding biopsy collection. Biopsies were dated according to stated last menstrual period (LMP) and confirmed by histological assessment according to published criteria (Noyes et al., 1950). Furthermore, circulating oestradiol and progesterone concentrations at the time of biopsy were consistent for both stated LMP and histological assignment of cycle stage.
Endometrial biopsies collected with a Pipelle sampler (Pipelle Laboratories CCD, Paris, France) were obtained from 25 fertile women with a regular menstrual cycle (25–35 days). The LH surge was determined using a commercially available home urine LH kit (Conceive; Quidel, San Diego, CA, USA). Detection of the LH surge, when basal levels of urinary LH doubled, was confirmed by radioimmunoassay of serum samples. In order to simulate luteal regression, 15 women self-administered progesterone (Cyclogest; Hoechst UK Ltd, Milton Keynes, Bucks, UK) in a dose of 200 mg twice daily from LH+8 for 4 days and an endometrial biopsy was conducted on: (i) LH peak + 8–10 days (n = 5), (ii) 24 h after cessation of progestogen (n = 5) and (iii) 48 h after cessation of progestogen (n = 5). As previously reported, this model demonstrated a significant fall in circulating progesterone concentration at 24 and 48 h post progestogen withdrawal (Critchley et al., 1999).
Endometrial biopsies were also obtained from five women who were administered human chorionic gonadotrophin (HCG) for 8 days (Critchley et al., 1999) from day LH+8, to stimulate very early pregnancy.
A previous study, completed within this laboratory, evaluated endometrial biopsies from women using the LNG-IUS (Critchley et al., 1998b). Archival endometrial biopsies were therefore identified from women who had self-determined breakthrough bleeding (n = 9) or no bleeding (n = 9) after at least 3 months post insertion of the LNG-IUS.
All tissue samples were collected in 4% neutral buffered formalin and fixed overnight at 4°C prior to wax embedding. Ethical approval was obtained from Lothian Research Ethics Committee (Ref. No. 1702/93/6/73 and 1702/94/6/1) and written informed consent was obtained from all subjects before tissue collection.
Localization of MMP-1 and mast cells by immunohistochemistry
A mouse monoclonal antibody raised against human mast cell tryptase (1:500; Dako Ltd, Ely, Cambs, UK) was used to localize mast cells, and a rabbit polyclonal antibody against the hinge region of MMP-1 (1:400; Sigma, Poole, Dorset, UK) was used to localize MMP-1. All immunohistochemical assays employed the technique previously described in detail by this laboratory (Jones et al., 1997). In brief, sections were dewaxed in Histoclear and hydrated in descending alcohol solutions, washed in phosphate-buffered saline and endogenous peroxidase activity was quenched with H2O2 (3% in distilled water). Non-immune horse serum was applied for 20 min before overnight incubation at 4°C with primary antibody. After secondary antibody application, an avidin-biotin peroxidase detection system was applied (Vector Lab., Burlingame, CA, USA) with 3,3'- diaminobenzidine (DAB) as the chromagen (appears brown). Sections were counterstained with Harris's haematoxylin (blue) before mounting. A mouse or rabbit IgG at the same concentration as the primary antibody (Vector Laboratories) was used as a negative control for each antibody. Procedures were carried out at room temperature unless otherwise specified.
Immunohistochemical co-localization of mast cell tryptase and MMP-1
Tissue slices were treated as above with both primary antibodies for mast cell tryptase and MMP-1 (1:50) added together as the primary antibodies and incubated overnight at 4°C. After washing, goat anti-mouse TRITC-labelled (red; mast cell tryptase) and goat anti-rabbit FITC-labelled (green; MMP-1) secondary antibodies (1:250; Sigma) were applied for 1 h at room temperature. The slides were then washed, mounted directly with Fluoromount and dried in the dark at 4°C before examination using a confocal scanning microscopy (Axiovert 100M; Zeiss Welwyn Garden City, Herts, UK).
Quantitative analysis of immunohistochemistry
Twelve separate digital images were photographed from each mast cell tryptase tissue section (this number ensured that the inter-image variance was below 5%). Using Openlab software (Improvision, Coventry, UK), a mask was generated for each colour (brown for DAB and blue for haematoxylin). The numbers of separate objects were then counted and mast cells or haematoxylin-stained nuclei were identified by selecting a minimum object size. The software then generated a cell number for both mast cells and total cell number (taken as the number of nuclei) from each image. These were averaged for each tissue section to give an overall cell number. Statistical analysis between groups was carried out using analysis of variance (ANOVA).
Semi-quantitative analysis of immunohistochemistry
Immunohistochemical localization of MMP-1 was present in too many cell types to allow quantitative analysis and was instead semi-quantitatively assessed as described previously (Critchley et al., 1998b). In brief, two separate observers ranked the staining on an arbitary scale (0 = no staining, 1 = occasional cell immunoreactivity; 2 = large number of cells stained; 3 = extensive immunostaining). Statistical analysis used ANOVA.
Results
Co-localization of mast cell tryptase and MMP-1
Co-localization studies using the same tissue section demonstrated that mast cells (positive for mast cell tryptase; red) were present as a diffuse population throughout the myometrium, and to a lesser extent in the basalis (Figure 1a and d). There is strong expression of MMP-1 (green) in a similar diffuse population of cells with additional expression in myometrial fibroblasts (Figure 1b and e). Amalgamation of the images demonstrates clear co-localization (yellow) of mast cell tryptase and MMP-1 within the same (yellow) intracellular granules (Figure 1c and f) in myometrial and basalis mast cells. Similar observations were seen in the functionalis layer but mast cells were dispersed more diffusely than the basalis (Figure 1h versus i). Furthermore, mast cells throughout the uterus always co-localized with MMP-1 irrespective of the menstrual cycle stage (data not shown). In some late secretory biopsies, mast cells were identified with both MMP-1 and mast cell tryptase localized in a more diffuse pattern (yellow) surrounding the cell indicating co-release of these products from mast cells (Figure 1g). Myometrial fibroblasts expressing MMP-1 can be seen surrounding this mast cell (Figure 1g). Co-localization experiments were also carried out in all the other tissue groups in this study and mast cell tryptase positive cells were always positive for MMP-1 (data not shown). All negative control sections showed no immunoreactivity (for representative section see Figure 1g inset).
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Evaluation of mast cell distribution
Endometrium and myometrial distribution of mast cells throughout the menstrual cycle
Myometrium contained the greatest number of mast cells when compared to the basalis and functionalis layers of the endometrium (Figure 1h
–j). Within the endometrium, the basalis contained more mast cells than the functionalis (Figure 1h and i). Subjective analysis of endometrial biopsies suggested that there was mast cell activation (defined by a more diffuse mast cell tryptase staining; Figure 1k versus l) in late secretory/early menstrual samples compared to other stages of the cycle. Quantitative analysis of mast cell numbers throughout the cycle was not attempted due to the difficulty involved in satisfactorily distinguishing clearly between the functionalis and basalis layers.
Mast cell numbers in an endometrial model simulating luteal regression
Occasional mast cells were present in the functionalis from control mid-secretory endometrial biopsies (Figure 2a). No significant difference in mast cell numbers was observed 24 or 48 h after withdrawal of progestogen (Figure 2a). Furthermore, no difference in mast cell activation was observed between the biopsy groups (data not shown).
|
Mast cells in stimulated early pregnancy
No increase in mast cell number was observed in endometrium from patients administered with HCG from day LH+8 when compared to mid-secretory endometrium (Figure 2a
). Additionally, no difference in mast cell activation was observed in this group (data not shown).
Endometrial mast cell distribution in LNG-IUS-treated patients: effect of breakthrough bleeding
The endometrium of patients with a LNG-IUS in utero developed a decidualized appearance (Figure 1m, n, q and r), as has previously been described (Critchley et al., 1998a). Comparison of mast cell distribution between the endometrial samples collected from the mid-luteal stage with those from simulated pregnancy (HCG-treated) and those with a LNG-IUS not experiencing breakthrough bleeding showed no significant differences. However, if the patients reported breakthrough bleeding mast cell numbers were significantly increased (P < 0.05) compared to those in endometrial tissue collected from women using a LNG-IUS and not reporting this side effect (Figure 1m versus n, and Figure 3a). Furthermore, the mast cells from patients reporting breakthrough bleeding were more frequently activated compared with those from the control LNG-IUS group (Figure 1m versus n).
|
Immunohistochemical localization of MMP-1
Endometrium and myometrial expression of MMP-1 throughout the menstrual cycle
Localization of MMP-1 by immunohistochemistry identified a diffuse population of cells, especially within the myometrium, which we identify as mast cells, as determined by co-localization using confocal microscopy (Figure 1b
, e and g). In addition, myometrial fibroblasts displayed positive immunoreactivity (Figure 1b and g). Increased MMP-1 expression throughout the endometrium was found in some late secretory/early menstrual biopsies (data not shown), as has previously been reported (Kokorine et al., 1996).
MMP-1 expression in an endometrium model simulating luteal regression
No MMP-1 immunoreactivity was observed in mid-luteal biopsies and, although immunostaining increased in stromal and glandular epithelial cells 48 h after progesterone withdrawal, these results did not reach statistical significance (Figure 1o versus p and 2b).
MMP-1 expression in simulated early pregnancy
Although decidualization involves profound differentiation of the endometrium, no increase in MMP-1 protein expression was noted in tissue exposed to HCG (Figure 2b).
MMP-1 expression in endometrium of patients with a LNG-IUS: effect of breakthrough bleeding
Increased overall MMP-1 immunostaining was observed in biopsies from women experiencing breakthrough bleeding compared to biopsies exposed to a LNG-IUS but without reported bleeding problems. However, the differences did not reach statistical significance (Figure 1q versus r and Figure 3b). Some peri-vascular localization of MMP-1 was observed in non-bleeding samples that may be related to decidualization. Samples from patients with breakthrough bleeding demonstrated predominately stromal MMP-1 immunoreactivity, although some glandular and vascular staining was also noted.
Discussion
In this study, we have demonstrated the presence of mast cells predominately in the myometrium of uterine tissue during the menstrual cycle. These mast cells and those present throughout the endometrium, as defined by the presence of mast cell tryptase, co-express MMP-1 and tryptase in the same intracellular secretory granules. Furthermore, both these proteolytic enzymes appear to be co-released into the surrounding extracellular milieu. Endometrial biopsies from women using a LNG-IUS and who experienced breakthrough bleeding displayed an increase in mast cell numbers. These data suggest that mast cell infiltration is related to breakthrough bleeding and may have less of a role in tissue breakdown at menstruation.
MMP-1 expression in the endometrial functionalis layer has previously been documented to be mainly restricted to superficial foci (Kokorine et al., 1996). Our present co-localization studies show a similar finding and identify mast cells as the stromal cell population which strongly express MMP-1. Confocal microscopy has confirmed that both MMP-1 and mast cell tryptase co-localize to the same granules and that upon mast cell activation both enzymes are co-released. A similar observation, using a co-localization technique, has also been demonstrated for mast cells present in atherosclerotic plaques (Johnson et al., 1998). However we are unaware of previous documentation of specific co-localization in human endometrial tissue. MMP-1 immunoreactivity was also found in myometrial fibroblasts throughout the cycle as previously observed (Ma and Chegini, 1999). Furthermore, little MMP-1 immunoreactivity was observed in the basalis and functionalis layers except when the tissue was undergoing premenstrual degradation.
The co-localization of MMP-1 and mast cell tryptase may be related to the enzyme activation cascade following their co-release from mast cells. Although these studies focused on tryptase-containing mast cells (the whole population), a subset of mast cells in endometrium also expresses chymase (Jeziorska et al., 1995; Mori et al., 1997). Mast cell chymase can activate both MMP-1 and MMP-3, whereas mast cell tryptase only activates MMP-3 (Lees et al., 1994). However, MMP-3 can itself activate MMP-1, and the co-release of these enzymes is likely to have a role in the cascade of MMP activation at sites of tissue degradation. Importantly, mast cell-conditioned medium has been found to increase stromal cell proMMP-1 and proMMP-3 expression (Zhang et al., 1998), further supporting a direct role for mast cell tryptase and chymase in tissue breakdown.
The role of the very large number of mast cells in the myometrium relative to the endometrium, however, remains unclear. It could be that these cells are operating as sentinel cells to help mediate uterine host defence systems. Alternatively, the myometrial mast cells may be the source of mast cells in the functionalis layer that are recruited to modulate tissue breakdown at menstruation (Jeziorska et al., 1995). Furthermore, there is also evidence that these myometrial mast cells are directly involved in mediating uterine contractions (Rudolph et al., 1993, 1997).
The role of progesterone in the modulation of endometrial mast cells has been examined using models of progesterone withdrawal in vivo and simulation of early pregnancy (Critchley et al., 1999). Previous reported data examining mast cells during the menstrual cycle in functionalis shows that mast cell numbers, and their activation, are up-regulated by progesterone withdrawal at the end of the cycle (Salamonsen and Woolley, 1996). We were unable to confirm this observation in our present study where we saw no change in mast cell numbers 48 h after progesterone withdrawal.
Together the above observations suggest that progesterone is not directly regulating mast cell traffic in the endometrium during the cycle, although progesterone does regulate MMP-1 expression by other cell types which may then affect mast cell activation (Jeziorska et al., 1995; Salamonsen and Woolley, 1996). Previous reports have supported this concept by showing that oestradiol and progesterone or synthetic progestins alone decrease secreted proMMP-1 in endometrial stromal cells and that administration of a progesterone antagonist, RU486, antagonizes these effects (Salamonsen et al., 1997; Lockwood et al., 1998; Hampton et al., 1999). In addition, medroxyprogesterone acetate has been shown to inhibit MMP-1 expression in cultured endometrial stromal cells (Schatz et al., 1999).
An increase in mast cells has been observed in patients experiencing breakthrough bleeding whilst using an LNG-IUS. Whether the mast cells in these situations originate from the myometrium or from ruptured blood vessels is difficult to discern. The role for progesterone in the regulation of mast cell trafficking throughout the uterus also remains to be determined. Nevertheless, in biopsies from patients reporting breakthrough bleeding, mast cells were consistently observed within the endometrium and were invariably in an activated state. One possible explanation is that long-term exposure to synthetic progestins results in desensitization of mast cells to the inhibitory effects of progesterone. The modest increase in mast cell numbers in the endometrium of women who report breakthrough bleeding whilst using a LNG-IUS supports this hypothesis. Further support for this concept comes from immunohistochemical experiments demonstrating increased mast cell activation in Norplant-treated patients, although no correlation was found with bleeding patterns (Vincent et al., 2000). Our data also implicate desensitization from the normal inhibitory effects of progestogen, as these women are exposed to high synthetic progestogen levels. It is of interest in this context that mast cells have been demonstrated to express the progesterone receptor (Letourneau et al., 1996). Whether the progesterone receptor is desensitized in patients with breakthrough bleeding is not clear but cystitis (increased mast cells in bladder tissue predominately in postmenopausal women) can be successfully treated by administration of progesterone-containing hormone replacement therapy (Letourneau et al., 1996; Theoharides et al., 1998).
The relationship between mast cells and MMP-1 production is likely to be multifactorial. We have clearly demonstrated, using confocal microscopy, that mast cells express MMP-1 and tryptase in the same intracellular granules and that myometrial fibroblasts also express MMP-1. We have shown a significant increase in mast cells in patients with bleeding problems and postulate that there is a fundamental difference in the role of mast cells in tissue breakdown seen after progesterone withdrawal compared to that in patients with breakthrough bleeding. Nevertheless, the large proportion of women who do not experience breakthrough bleeding with progestogen-only contraception, for example the LNG-IUS, indicates an endogenous resistance in the population to the possible deleterious side-effects of high levels of local progestogen.
Acknowledgements
Support was provided by the project grants to HODC from The Wellcome Trust (No. 0044744/Z/95/Z) and MRC (No. G9620138) and to SCR from The Scottish Hospital Endowment's Research Trust (No. 1389).
Notes
1 To whom correspondence should be addressed at: MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh, EH3 9ET, UK. E-mail: Stuart.Milne{at}hrsu.mrc.ac.uk 
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Submitted on December 11, 2000; accepted on March 22, 2001.
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