Molecular Human Reproduction, Vol. 5, No. 10, 950-954,
October 1999
© 1999 European Society of Human Reproduction and Embryology
Molecular events in the endometrium |
Regulation of matrix metalloproteinases (MMPs) and their tissue inhibitors in human myometrial smooth muscle cells by TGF-ß1
Department of Obstetrics and Gynecology, University of Florida, Gainesville, FL 32610, USA
Abstract
The objective of the present study was to determine whether transforming growth factor ß (TGF-ß) regulates the expression of matrix metalloproteinases (MMP) and the tissue inhibitor of MMP (TIMP) in myometrial smooth muscle cells. Using primary cultures of human myometrial smooth muscle cells we found that these cells express MMP-1, MMP-3, TIMP-1 and TIMP-2 mRNA and protein, with significantly higher values of TIMP than MMP. We also found that TGF-ß1 (1 ng/ml) increased the expression of TIMP-1 mRNA, while it reduced the expression of MMP-1 and MMP-3 mRNA, compared with untreated controls. In addition, TGF-ß1 slightly increased the production of TIMP-1, but not TIMP-2. Production of MMP-1 and MMP-3 was reduced by treatment with TGF-ß1, compared with the untreated control. A major portion of MMP-1 released into the culture-conditioned media was in complex with TIMP-1, and the levels of this complex were reduced by treatment with TGF-ß1. In conclusion, the data indicate that myometrial smooth muscle cells express MMP and TIMP mRNA and protein, and their expression is differentially regulated by TGF-ß1. Such a differential regulation of MMP and TIMP by TGF-ß may influence the rate of extracellular matrix (ECM) turnover following tissue injury, induced during myomectomy and Caesarean section, or in leiomyomas during growth.
MMP/myometrial smooth muscle cells/TIMP/transforming growth factor ß (TGF-ß)
Introduction
Myometrium is a quiescent tissue, and under normal conditions undergoes little or no architectural changes during the menstrual cycle. However, it undergoes extensive tissue remodelling during pregnancy and parturition, and following tissue trauma induced during myomectomy and Caesarean section, events that are major causes of peritoneal adhesion formation. Transforming growth factor ß (TGF-ß), and its over-expression, is considered critical in tissue remodelling and scar tissue formation, including peritoneal adhesions (Border and Nobel, 1994; Roberts, 1995
; Chegini, 1997). The effect of TGF-ß on this process occurs partly through a mechanism involving stimulation of mesenchymal cell migration, their proliferation, synthesis and deposition of extracellular matrix (ECM), and inhibition of proteolytic enzyme expression that degrades ECM (Hay, 1991; Mosher et al., 1992; Clark, 1996; Lawrence, 1996).
Among the major proteolytic enzymes involved in ECM degradation are matrix metalloproteinases (MMP). These enzymes are either not constitutively expressed, or expressed minimally in normal adult tissues; however, they are induced in tissues that normally undergo extensive remodelling, e.g. endometrium, the wound environment, and in response to various inflammatory conditions (Marbaix et al., 1996; Mignatti et al., 1996; Salamonsen, 1996; Hulboy et al., 1997). The proteolytic activity of these enzymes is partly regulated by tissue inhibitors of MMPs (TIMPs), which are expressed in a wide variety of tissues (Overall, 1994; Mignatti et al., 1996; Hulboy et al., 1997). The expression of MMPs and TIMPs is regulated at several levels, and is influenced by many growth factors, pro-inflammatory cytokines and hormones, including TGF-ß (Mignatti et al., 1996; Hulboy et al., 1997).
We have previously reported that myometrium expresses TGF-ß, MMP and TIMP mRNA and protein (Dou et al., 1996, 1997; Tang et al., 1997). We have also reported that TGF-ß, MMP and TIMP expression is regulated differently in myometrium and leiomyomas in women who received gonadotrophin-releasing hormone agonist (GnRHa) therapy to induce leiomyoma regression, compared with untreated groups (Dou et al., 1996, 1997; Chegini, 1999); and in myometrium of women who failed labour induction, had no labour or had preterm labour (unpublished data). Under these conditions, and following tissue injury induced during myomectomy and Caesarean section, the myometrium undergoes extensive tissue remodelling. Tissue injury caused by myomectomy and Caesarian section is also a leading cause of peritoneal adhesion formation, a condition associated with over- expression of TGF-ß (Williams et al., 1992; Chegini, 1997; Lucas et al., 1997; Rong et al., 1997; Chegini et al., 1999). The aim of this study was to determine whether TGF-ß regulates the expression of MMPs and TIMPs in myometrial smooth muscle cells, a possible mechanism which may influence the rate of ECM turnover in myometrium and leiomyomas.
Materials and methods
All the materials and procedures for isolation and culture of myometrial smooth muscle cells, reverse transcription–polymerase reaction (RT–PCR), and construction of the external cDNA standard template for quantitative RT–PCR and enzyme-linked immunosorbent assay (ELISA) have been previously described (Dou et al., 1996, 1997; Tang et al., 1997). Human specific MMP-1, MMP-3, TIMP-1, TIMP-2 and MMP-1/TIMP-1 complex ELISA kits with detection limits of 1.7, 2.3, 1.3, 3 and 1.5 ng/ml respectively, were purchased from Oncogene Sciences Inc (Cambridge, MA, USA). Primary culture of myometrial smooth muscle cells were established using portions of myometrial tissue obtained from premenopausal women who were undergoing hysterectomy for benign gynaecological conditions. Collection of the tissues for this study was approved by the Institutional Review Board.
Myometrial smooth muscle cells were seeded at a density of 106 cells/well in 6-well plates with Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) for 48 h or until reaching ~80–90% confluency. The cells were washed and incubated in serum-free media for 24 h, washed again, and then exposed to 1 ng/ml of recombinant human TGF-ß1 (R&D, Minneapolis, MI, USA) in medium containing 2% FBS for 2, 6, 12, 24 and 48 h. After incubation, the culture-conditioned media and cells were collected and immediately processed for ELISA and quantitative RT–PCR respectively.
To determine the expression of MMP and TIMP mRNA and their regulation by TGF-ß1, total RNA was isolated from TGF-ß1-treated and untreated smooth muscle cells and subjected to quantitative RT–PCR as previously described (Dou et al., 1997; Tang et al., 1997). For quantitative RT–PCR, cDNA was synthesized in a series of standard reactions each containing 2 µg of total cellular RNA and several dilutions of competitive external cRNA standard (103 to 108 copies/reaction). The PCR products were separated on 2% agarose gels containing ethidium bromide and photographed on a Kodak 120 digital camera. The band intensities were determined and the values were normalized for molecular weight. The ratio of the band intensities was plotted against the copy number of cRNA standard/ reaction and analysed by equation of best fit lines (Dou et al., 1997, 1999). The final mRNA quantity was determined where the ratio of template/target band intensities was equal to 1 and reported as copies mRNA/µg of total RNA, as previously described (Dou et al., 1999).
To determine whether smooth muscle cells produce MMPs and TIMPs, and if their production is regulated by TGF-ß1, culture-conditioned media from TGF-ß1-treated and untreated cells were collected and centrifuged at 1500 g for 10 min, and the supernatants were assayed for MMP-1, MMP-3, TIMP-1, TIMP-2 and the MMP-1/TIMP-1 complex by ELISA, according to the manufacturer's recommended procedure.
All the measurements were performed in duplicate from three independent cell cultures. The data are presented as mean ± SEM and statistical analyses were performed using unpaired Student's t-test and Kruskal–Wallis one way analysis of variance with Dunn test, using computer software program SigmaStat (Jandel Co, San Rafael, CA, USA). P < 0.05 was considered to be statistically significant.
Results
Myometrial smooth muscle cells express MMP-1, MMP-3, TIMP-1 and TIMP-2 mRNA and protein determined by quantitative RT–PCR and ELISA (Figures 1–4). Under the culture conditions of this study, these cells expressed significantly higher levels of TIMPs than MMPs, and higher TIMP-1 than TIMP-2 mRNA (Figures 1 and 2). In the presence of TGF-ß1, there was a reduction in MMP-1 mRNA expression from 5.4 ± 1.3x106 copies/µg of total RNA (after 6 h) to 2.2 ± 0.5x106 copies after 12 h of incubation (P < 0.05). However, the expression of MMP-3 mRNA increased from 1.3 ± 0.3x106 to 3.3 ± 0.9x106 copies after 6–12 h of incubation in the presence of TGF-ß1. These values were significantly lower than those expressed by the untreated controls during the same period (1 ± 0.5x107 versus 4.3 ± 1.6x107 copies; Figure 2, P < 0.05). TGF-ß1 treatment also increased the expression of TIMP-1 and TIMP-2 mRNA (Figure 2). TIMP-1 levels were significantly higher than untreated controls after 12 h of treatment (9.6 ± 2.5x109 copies versus 1.04 ± 4.7x108, P < 0.05), but there was no significant difference between TGF-ß1-treated and untreated controls, with regard to TIMP-2 expression.
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) and untreated (o) myometrial smooth muscle cells after 6 and 12 h of incubation. MMP-1 (a versus b, significantly different; P < 0.05), MMP-3 (c versus d and e versus f, significantly different; P < 0.05), TIMP-1 (a versus b and b versus c, significantly different; P < 0.05) and TIMP-2 (d versus e, significantly different; P < 0.05).
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The myometrial smooth muscle cells released very low levels of MMP-1 and MMP-3 into their culture-conditioned media. These values were significantly increased during the 6–24 h of incubation for MMP-1 and up to 48 h for MMP-3 (Figure 3
). However, these levels were significantly lower following treatment with TGF-ß1 during the 6–24 h of incubation for MMP-1 (P = 0.05 and 0.01), and 12–48 h for MMP-3 (P = 0.02, Figure 3). The smooth muscle cells also produced significantly more TIMP-1 than TIMP-2 (P = 0.001, Figure 4). There was a steady state (five-fold) increase in TIMP-1, but not TIMP-2 production during the 48 h incubation; however, the effect of TGF-ß1 on TIMP-1 production was only different from control after 24 h of treatment (P = 0.03; Figure 4). Since the assays measure total MMP-1 (both free MMP-1 and complexed with TIMP-1, but not with 
2-macroglobulin), total MMP-3 (pro and active MMP-3, and MMP-3/TIMP complex) and total TIMPs (free and complexed with MMP), we determined the MMP1/TIMP-1 complex in culture-conditioned media in TGF-ß1-treated and untreated cells. The conditioned media of the untreated smooth muscle cells contained MMP-1/TIMP-1 complex, which steadily increased during the 48 h of treatment with TGF-ß1, and 12–24 h of incubation in the control group (P = 0.01 and 0.02). Treatment with TGF-ß1 reduced the levels of MMP-1/TIMP-1 complex, in comparison with controls (Figure 4). Discussion
In the present study, we found that myometrial smooth muscle cells express MMP-1 (or interstitial collagenase) which degrades type I, II, III and VII collagens, and MMP-3 (or stromalysin 1) which degrades fibronectin, laminin, proteoglycans and collagens III, IV and V. Although these cells express relatively similar levels of MMP-1 and MMP-3 mRNA, they produce very low to undetectable levels of MMP-1 and MMP-3 in culture-conditioned media. This suggests that MMP-1 and MMP-3 expression in myometrial smooth muscle cells is either regulated post-transcriptionally, or these cells do not release, but rather retain the MMPs intra-cellularly (possibly as proenzymes), because of the presence of immunoreactive MMP-1 and MMP-3 in these cells (Dou et al., 1997).
The expression of MMPs in adult tissues has been reported to be low, or not constitutively expressed. However, MMPs are induced in tissues that normally undergo extensive remodelling, e.g. endometrium during the menstrual cycle, the wound environment, and in tissue response to various inflammatory conditions (Mignatti et al., 1996; Salamonsen, 1996; Hulboy et al., 1997). Under in-vitro conditions, various cell types isolated from these tissues express MMPs, and several pro-inflammatory cytokines, growth factors and hormones including TGF-ß have been shown to regulate their expression (Wright et al., 1991; Winsor et al., 1993; Mignatti et al., 1996; Hulboy et al, 1997; Singer et al, 1997). In myometrial smooth muscle cells, our data indicate that TGF-ß1 inhibits the expression of MMP-1 and MMP-3 mRNA expression, in comparison with untreated controls. However, the MMP-3 mRNA expression in the presence of TGF-ß1 did not change significantly between 6 and 12 h of incubation, suggesting stability in MMP-3 expression. At the protein level, TGF-ß inhibited the levels of MMP-1 and MMP-3 released into the culture-conditioned media when individually compared with the untreated controls at various time points. However, there was a steady state increase in MMP-1 and MM-3 production in both the untreated and TGF-ß1-treated myometrial smooth muscle cells, suggesting that TGF-ß1 may delay, rather than inhibit, their production. This effect may be attributed to the presence of 2% serum in the culture-conditioned media, which contain various factors that could interfere with TGF-ß1 action. TGF-ß has been shown to inhibit the expression of MMPs in other cells types, including MMP-3 in fibroblasts, MMP-7 in endometrial epithelial cells, and MMP-1 and MMP-3 in mesothelial cells and macrophages (Bruner et al., 1995; Mignatti et al., 1996; Hulboy et al., 1997; C. Ma et al., unpublished data). In endometrial stromal cells, the inhibitory action of progestin on MMP-7 expression may be mediated through progesterone-induced TGF-ß expression (Bruner et al., 1995).
Unlike MMPs, TIMPs are expressed in many adult tissues, and their expression is regulated in co-ordination with MMPs (Mignatti et al., 1996; Gomez et al., 1997; Hulboy et al., 1997). Our data indicate that myometrial smooth muscle cells express more TIMP-1 mRNA than TIMP-2, and that these levels are ~10–100-fold higher than MMP-1 and MMP-3 expression. These cells also produce a significantly more TIMP-1 than TIMP-2, which was found at low to undetectable levels. This suggests that TIMP expression in myometrial smooth muscle cells is differentially regulated, possibly at the post-trancriptional level. Due to higher TIMP-1 production by myometrial smooth muscle cells, TIMP-1 rather than TIMP-2, may be involved in inhibiting the catalytic activity of MMPs in myometrial tissue. Our data also suggest that TGF-ß1 regulates the expression of TIMP-1 mRNA, with a limited effect on TIMP-1 and TIMP-2 protein production. As myometrial smooth muscle cells produce more TIMP-1 than MMPs, and most of the MMPs appear to be in complex with TIMP-1 (MMP-1/TIMP-1 complex), such a condition in vivo may allow limited or no proteolytic enzyme activity leading to deposition rather than degradation of ECM. This condition may occur following tissue injury during myomectomy and Caesarean section, events known to cause peritoneal adhesion formation, characterized by excess deposition of ECM. In leiomyomas which over-express ECM, we have previously reported a direct correlation between TGF-ß and TIMP expression, but an inverse relationship with MMP expression, in comparison with myometrium (Dou et al., 1996, 1997). During pregnancy and parturition in which myometrium undergoes extensive tissue remodelling, we have also demonstrated that myometrium from women who had failed labour induction express different amounts of TGF-ß1 and TGF-ß receptors, compared with women who had undergone no labour (unpublished data). Surgically-induced uterine injury which is associated with over-expression of TGF-ß also leads to development of peritoneal adhesions (Chegini, 1997; Chegini et al., 1999). This condition often occurs following tissue injury during myomectomy and Caesarean section, the leading causes of peritoneal adhesion formation.
In summary, the data provide further evidence that myometrial smooth muscle cells express MMPs and TIMPs, and suggest that their expression is differently regulated by TGF-ß1. Such differential regulation of MMPs and TIMPs may serve as a mechanism which influences myometrial tissue remodelling during pregnancy or following tissue injury.
Notes
1 To whom correspondence should be addressed 
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Submitted on April 7, 1999; accepted on June 22, 1999.
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