RETRACTED: Expression of matrix metalloproteinase-26 (MMP-26) mRNA in mouse uterus during the estrous cycle and early pregnancy

Life Sciences 77 (2005) 3355 – 3365 www.elsevier.com/locate/lifescie

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Expression of matrix metalloproteinase-26 (MMP-26) mRNA in mouse uterus during the estrous cycle and early pregnancy Guoyi Liu a,b, Xuan Zhang a, Haiyan Lin a, Qinglei Li a, Hongmei Wang a, Jiang Ni b, Qing-Xiang Amy Sang c, Cheng Zhu a,T a

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 25 Bei Si Huan Xi Lu, Beijing 100080, People’s Republic of China b Laboratory of Reproductive Endocrinology, Department of Physiology, Harbin Medical University, Harbin 150086, People’s Republic of China c Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306-4390, United States Received 9 December 2004; accepted 9 May 2005

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Abstract

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Matrix metalloproteinases (MMPs) and their tissue inhibitors play important roles in the remodeling of extracellular matrix (ECM). MMP-26, also called endometase or matrilysin-2, is a novel member of the MMP family. The present study was to investigate the temporal and spatial expression of MMP-26 mRNA in mouse uterus during the estrous cycle and early pregnancy by using in situ hybridization and semi-quantitative RT-PCR. In this study, MMP-26 mRNA was found to be localized to the luminal and glandular epithelium at proestrus and estrus, and the expression level was decreased significantly from metestrus to dioestrus. During pre-implantation period, MMP-26 mRNA was predominantly expressed in luminal and glandular epithelium at much higher level; whereas it switched to stroma during peri-implantation period, and also appeared in the blastocysts and the implantation sites. The results suggested that MMP-26 might play a role in the cycling changes of mouse uterus during the estrous cycle and embryo implantation. D 2005 Elsevier Inc. All rights reserved. Keywords: MMP-26; Mouse; Uterus; Estrous cycle; Implantation

T Corresponding author. Tel.: +86 10 62555872; fax: +86 10 62529248. E-mail address: [email protected] (C. Zhu). 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.05.045

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Introduction

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The mammalian uterus is a unique dynamic organ composed of heterogeneous cell-types, mainly including luminal and glandular epithelium, stroma and endothelium. During the estrous/menstrual cycle and the establishment of pregnancy, the uterus undergoes remarkable cyclic growth, differentiation, breakdown and remodeling in response to fluctuations in steroid hormone concentrations. A large body of evidence indicates that the degradation and re-synthesis of the ECM components, which is essential for the endometrial breakdown and remodeling, could be affected by a variety of proteinases, cytokines, and growth factors (Das et al., 1994; Lim et al., 1999; Tabibzadeh, 2002; Liu et al., 2004). MMPs are a family of zinc proteinases that are responsible for the degradation of ECM and may participate in many physiological and pathological processes. Accumulating experimental data, including our previous studies, suggested that MMPs play important roles in female reproduction (Hurst and Palmay, 1999; Paria et al., 2000; Wang et al., 2001; Zhang et al., 2004). MMP-26, also called endometase or matrilysin-2, is a novel member of the MMP family (De Coignac et al., 2000). It was initially cloned from a human endometrial tumor cDNA library (Park et al., 2000). Its prepro-enzyme has 261 amino acid residues and lacks a hemopexin-like domain, making it the smallest member of the MMP family, with a molecular mass of 28 kDa. The primary structure of MMP-26 can be divided into three regions, including a signal peptide, a propeptide domain, and a catalytic domain. It has a unique cysteine switch sequence, PHCGVPDGSD, and a zinc-binding consensus sequence in the catalytic domain. MMP-26 exhibits wide substrate specificity in cleaving ECM and basement membrane proteins. Its substrates include type-I gelatin, human plasma a1-proteinase inhibitor type-IV collagen, fibrinogen, fibronectin and vitronectin (Park et al., 2002; Uria and Lopez-Otin, 2000; Marchenko et al., 2001). MMP-26 exhibited a very restricted pattern in human tissues, and was found to be specific to the uterus and placenta. It was also reported that MMP-26 was primarily expressed in epithelial cancers such as lung, breast, endometrial and prostate carcinomas and in the corresponding tumor cell lines (De Coignac et al., 2000; Park et al., 2000; Uria and Lopez-Otin, 2000; Marchenko et al., 2001; Chegini et al., 2003). At present, only several studies have examined the expression of MMP-26 in human endometrium and endometrial carcinoma (Chegini et al., 2003; Goffin et al., 2003; Isaka et al., 2003; Pilka et al., 2003, 2004a,b). To further understand the role of MMP-26 in uterus, the temporal and spatial expression patterns of MMP-26 transcripts in mouse uterus during the estrous cycle and early pregnancy were investigated by using in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR).

Materials and methods Animals and tissue preparation All procedures involving animals were carried out in accordance with the Policy on the Care and Use of Animals of the Ethical Committee, State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences.

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Adult male and female mice of Kunming White strain used in the experiments were bred randomly at room temperature (about 25 8C) with controlled light cycles (12 L : 12 D, lights on at 0600 h) and allowed free access to food and water. The various stages of the estrous cycle were determined by vaginal smears, and uteri of three mice were collected at each stage. To set up mating, two female mice were caged with a male overnight. The day of the vaginal plug being found was designated as day 1 of pregnancy. Pregnant uteri were collected on days 1~7 of pregnancy (n = 3 at each time point). Cyclic and pregnant uteri were divided into two parts, respectively. One part was snap-frozen in liquid nitrogen and stored at 80 8C for RNA extraction and the other was immediately embedded in embedding medium (Triangle Biomedical Sciences, Durham, NC, USA) and stored at 20 8C for in situ hybridization. Isolation of mRNA and semi-quantitative RT-PCR analysis

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Total RNA was extracted from the mouse uteri with Trizol reagent (Gibco BRL Life Technologies Inc., Rockville, MD, USA) according to the manufacturer’s instruction. The cDNA was synthesized from 2 Ag of total RNA using Superscript II reverse transcriptase (Invitrogen Inc., Rockville, MD, US). The reaction was carried out at 42 8C for 50 min and 70 8C for 15 min. The resulting cDNA samples were amplified by 25 cycles (denaturing at 94 8C for 45 s, annealing at 55 8C for 45 s, and elongating at 72 8C for 45 s) using MMP-26 primers (antisense primer 5VGCCCACTGCCAGAAAGAAACC-3Vand sense primer 5V-TCCATCGGAATGGGACAGACC-3V). The 25 Al PCR system contained 2 Al of reverse transcription products, 200 Amol/L of dNTPs, 2 mmol/L of MgCl2, 1U of Taq polymerase and 10 pmol of each MMP-26 primer. The anticipated size of the amplified fragment was 289 bp. The PCR system devoid of template cDNA was included as negative control. h-actin was amplified as internal control (primers were 5V-GTGGGGCGCCCCAGGCACCA-3V and 5V-CTCCTTAATGTCACGCACGATTTC-3V) with the expected size of 548 bp. The PCR products were electrophoresed on a 1% (w/v) agarose gel containing 0.5 Ag/ml ethidium bromide, and the sizes of the products were determined by comparison with a 2-kD DNA marker (Takaka, Corp. Dalian, China). All the PCR reactions were repeated at least three times. The intensity of each band amplified by RT-PCR was analyzed using MetaView image analyzing system (version 4.50, Universal Imaging Corp., USA), and normalized to that of h-actin mRNA in corresponding samples. The relative levels of MMP-26/h-actin mRNA were calculated. In situ hybridization

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The 289 bp amplified fragment for MMP-26 was recovered from the agarose gel, and purified using CONCERTTM Rapid Gel Extraction system (Gibco BRL Life Technologies Inc., Rockville, MD, USA). Then the fragment was inserted into pGEMR-T easy vector. To generate antisense cRNA probe, the plasmid was linearized with Sal I and in vitro transcribed with T7 RNA polymerase (Promega Corp., Madison, WI, USA); while the sense probe was synthesized using Nco I and SP6 RNA polymerase (Promega Corp., Madison, WI, USA). The cRNA probes were labeled with digoxigenin (DIG) RNA labeling mix (Roche Molecular Biochemicals, Mennheim, Germany). Cryosections (10 Am) on poly-l-lysine coated slides were quickly thawed and fixed in 4% paraformaldehyde for 15 min at room temperature. The slides were washed for 2  15 min in PBS containing 0.1% active DEPC, and then in 5  SSC (1  SSC is 0.15 M NaCl, 0.015 M sodium citrate) for 15 min. Prehybridization was carried out at 56 8C for 2 h in prehybridization solution containing 50%

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deionized formamide, 5  SSC, and 120 Ag/ml salmon sperm DNA (Sigma Chemical Co., St. Louis, MO, USA). The slides were then hybridized with 400 ng /ml of Dig-labeled probes in prehybridization buffer overnight at 50 8C in a moist chamber. Then the slides were serially washed in 2  SSC at room temperature for 30 min, in 2  SSC at 65 8C for 1 h, and in 0.1  SSC at 65 8C for 1 h. The slides were incubated with anti-DIG-alkaline phosphatase (diluted 1 : 5000) for 2 h at room temperature, and then rinsed twice for 15 min each in washing buffer (100 mM Tris, 150 mM NaCl, pH 7.5). Color development was carried out using NBT-BCIP (Boehringer-Mannheim, Indianapolis, IN, USA). The sense probes were used as negative controls for background levels. The results were recorded with SPOT digital camera system (Diagnostic Instruments, Inc., USA). Semi-quantitative analysis of in situ hybridization signals was performed using the method described by Liu et al. (2003). Signal intensity of MMP-26 mRNAs in different compartments of the uterus was quantified using the computer-aided laser scanning densitometry (Personal Densitometer SI; Molecular

Fig. 1. a) In situ hybridization for MMP-26 mRNA in mouse uterus during the estrous cycle. (A) dioestrus; (B) proestrus; (C) estrus; (D) metestrus. le, luminal epithelium; ge, glandular epithelium; st, stroma. Bar = 100 Am. b) Semi-quantitative analysis of the hybridization signals of MMP-26 mRNAs in different compartments of the uterus during the estrous cycle. Signal intensity was measured as the gray level within a given marked area that was above a preset gray threshold level. D, dioestrus; P, proestrus; E, estrus; M, metestrus.

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Statistical analysis

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Dynamics, Sunnyvale, CA). In order to make the semi-quantitative analysis credible in each sample, above 12 spots were randomly selected in luminal epithelium, glandular epithelium and stroma (decidua) for the sections hybridized to the antisense and sense probes. Specific signal intensity was defined as the average intensity for a section hybridized to the antisense probe minus the average intensity to the sense probe. Hybridization intensity was measured as the gray level within a given marked area that was above a preset gray threshold level.

All values are presented as mean F SEM. Statistical comparisons among groups were analyzed by one-way ANOVA followed by LSD test using SPSS software package (version 10.0.1, SPSS Inc., Chicago, IL, USA). A value of P b 0.05 was considered significant.

Results

Expression of MMP-26 mRNA in mouse uterus during the estrous cycle

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The expression pattern of MMP-26 mRNA in mouse uterus during the estrous cycle was investigated by in situ hybridization. Sense probes showed no specific hybridization signals in any sample investigated (data not shown). Representative sections from in situ hybridization study were shown in Fig. 1a. Semi-quantitative analysis of the hybridization signals in different compartments of the uterus

Fig. 2. Expression of MMP-26 mRNA in mouse uterus during the estrous cycle detected by RT-PCR. (a) Agarose-gel electrophoresis of MMP-26 and h-actin at dioestrus (D), proestrus (P), estrus (E) and metestrus (M). (b) Graphical illustrations of MMP-26 mRNA relative levels in mouse uteri at dioestrus, proestrus, estrus and metestrus (n = 9). Values are presented as ratio of densitometric readings of MMP-26 samples to corresponding h-actin samples.

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Fig. 4. Relative mRNA expression levels of MMP-26 in mouse uterus during early pregnancy detected by RT-PCR. (a) Agarose-gel electrophoresis of MMP-26 and h-actin on days 1–7 of pregnancy. (b) Graphical illustrations of MMP-26 mRNA relative levels in mouse uteri on days 1–7 of pregnancy (n = 9). Values are presented as ratio of densitometric readings of MMP26 samples to corresponding h-actin samples.

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was shown in Fig. 1b. The hybridization signals of MMP-26 mRNA were presented in mouse uteri throughout the estrous cycle. MMP-26 transcripts were predominantly detected in the luminal and glandular epithelium (Fig. 1a, A), whereas the level of MMP-26 mRNA was increased remarkably at estrus and metestrus (Fig. 1a, B and C; Fig. 1b) ( P b 0.05). During metestrus, the expression of signals in the stroma was higher than those of other stages (Fig. 1a, D; Fig. 1b), but there was no significant difference among the four stages ( P N 0.05). To gain an overview of the expression and variation of total MMP-26 mRNA in mouse uteri at various stages of the estrous cycle, semi-quantitative RT-PCR was used to examine relative changes of MMP-26 mRNA. The anticipated 289bp fragment of MMP-26 was detected in all of the uteri at various stages of the estrous cycle. No specific band was amplified in the negative control. Representative pictures of PCR-amplified products were shown in Fig. 2a. Computer-aided densitometric analysis of the amplified bands showed that MMP-26 mRNA levels at proestrus and estrus were higher than those at dioestrus and metestrus ( P b 0.05), and there was no significant difference between the signal levels at proestrus and estrus, and between those at dioestrus and metestrus, respectively ( P N 0.05) (Fig. 2b). Fig. 3. a) In situ hybridization for MMP-26 mRNA in mouse uterus during early pregnancy. (A~ G), days 1~7; H, day 1, sense; le, luminal epithelium; ge, glandular epithelium; st, stroma; PDZ, primary decidual zone; SDZ, secondary decidual zone; bl, blastocyst. Bar = 200 Am. b) Semi-quantitative analysis of the hybridization signals of MMP-26 mRNAs in different compartments of the uterus during early pregnancy. Signal intensity was measured as the gray level within a given marked area that was above a preset gray threshold level.1~7, days 1~7 of pregnancy.

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Expression of MMP-26 mRNA in mouse uterus during early pregnancy

Discussion

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MMP-26 mRNA localization in mouse uterus on days 1~7 of pregnancy was shown by in situ hybridization (Fig. 3a). Semi-quantitative analysis of the hybridization signals in different compartments of the uterus was shown in Fig. 3b. The signals for MMP-26 mRNA were mainly distributed to the luminal and glandular epithelium on day 1 and day 2 of pregnancy (Fig. 3a, A, B). Weak signals were presented in the subluminal epithelial stroma on days 1~3 (Fig. 3a, A, B, C). However, the signals were decreased in the luminal and glandular epithelium on days 3~4 ( P b 0.05), whereas increased dramatically in the stroma adjacent to the luminal epithelium on day 4 (Fig. 3a, D) ( P b 0.05). After implantation, MMP-26 transcripts were mainly present in primary decidual zone (PDZ) (Fig. 3a, E). Expression of MMP-26 was detected throughout the decidua on day 6. It was found that strong MMP-26 mRNA signals appeared in secondary decidual zone (SDZ) on days 6~7 (Fig. 3a, F). MMP-26 mRNA was also expressed strongly in the blastocyst (Fig. 3a, G). RT-PCR was performed to examine the expression of MMP-26 mRNA and h-actin in mouse uterus during early pregnancy. The predicted 289 bp fragment was obtained with MMP-26 primers (Fig. 4a). Densitometric analysis of RT-PCR revealed that the expression levels of MMP-26 mRNA were not substantially stable on days 1~7. The levels of MMP-26 mRNA were dramatically higher on days 4~7 than those on days 1~3 ( P b 0.05), there was no significant difference among the levels of hybridization signals on days 1~3 and on days 4~7, respectively ( P N 0.05) (Fig. 4b).

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MMPs are a family of highly homologous zinc metalloenzymes that degrade ECM proteins and process pro-growth factors and cytokines, and their activities are inhibited by tissue inhibitors of metalloproteinases (TIMPs) (Nagase and Woessner, 1999). The cyclic proliferation, angiogenesis, secretory differentiation, predecidua formation, inflammatory cell infiltration, extensive apoptosis, and tissue breakdown of the endometrium are associated with a coordinated selective up-and downexpression of MMPs and TIMPs (Goffin et al., 2003). MMP-26, a newly identified MMP, was the smallest member of this family. In an attempt to understand the roles of MMP-26 in reproductive system, the present study was undertaken to investigate the localization of MMP-26 mRNA in mouse uterus during the estrous cycle and early pregnancy. It is well known that the fluctuation of ovarian steroids during the estrous cycle causes the uterus to undergo extensive degrading and remodeling. In mice, serum estrogen concentration reaches a peak at the proestrus stage, is maintained at estrus, and declines to a low level at metestrus and dioestrus (Fata et al., 2001). The current study showed that MMP-26 mRNA appeared intensively in the luminal and glandular epithelium at proestrus, the stage of epithelial proliferation and remodeling, and then declined sharply from metestrus to dioestrus, which was consistent with the fluctuation of ovarian steroids. During human menstrual cycle, MMP-26 was expressed in endometrium and displayed menstrual cycle-dependent expression, with the highest levels occurring early- to mid-secretory phase (Chegini et al., 2003). Studies in human demonstrated that expression of MMP-26 was enhanced during the proliferative phase, and reached the peak level during early-secretory phase of the menstrual cycle, and endometrial surface and glandular epithelial cells were the major sites of MMP-26 (Goffin et al., 2003; Pilka et al., 2003). Thus, MMP-26 may

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play some specific roles in the cyclic changes of the uterus during the estrous cycle and menstrual cycle. Embryo implantation is a key event in the establishment of pregnancy. Successful embryo implantation depends on the synchronized development of both the invasiveness of the embryo and the receptivity of the endometrium. This process is accompanied by extensive degradation and remodeling of the ECM. The initial attachment reaction between the uterine luminal epithelium and the blastocyst trophectoderm in mouse occurs at 2200–2300 h on day 4 of pregnancy. Following the attachment reaction, uterine epithelial cells undergo extensive proliferation and differentiation into decidual cells (decidualization) at the site of blastocyst apposition (Das et al., 1994). The MMPs are responsible for the degradation of basement membrane and ECM, which is required for the invasive processes necessary to establish pregnancy (Osteen et al., 1997; Qin et al., 1997). The present research showed that MMP-26 mRNA was expressed by uterine luminal and glandular epithelium from day 1 to day 3, suggesting that MMP-26 was involved in the proliferation and differentiation of uterine epithelial cells during pre-implantation. However, the hybridization signals of MMP-26 mRNA was dramatically increased from day 4 and maintained at high level throughout peri-implantation stage, while the signals switched from epithelium to stroma, which showed that MMP-26 might be involved in the changes of the uterus during implantation. MMP-26 mRNA was detected in uterine stromal cells undergoing decidualization, a process involving proliferation, cellular growth, and differentiation. It was also present in the blastocysts and at implantation sites, suggesting that it may play a role in remodeling of ECM and invasion of cytotrophoblast into endometrium. In rhesus monkey, MMP-26 mRNA and protein were both expressed in endometrial compartments, with intense signals in the glandular epithelium on day 12 of pregnancy and in the walls of spiral arterioles adjacent to the implantation site on day 26 (Li et al., 2002). Taken together, the results indicated that MMP-26 was involved in the highly regulated remodeling of ECM, decidualization and invasion during early pregnancy. It has been confirmed that MMP-26 shares with MMP-7 the minimal domain organization required for secretion, latency, and catalytic activity of these enzymes. It also shares with MMP-7 other structural features as well as wide substrate specificity against protein components of ECM and basement membranes (Uria and Lopez-Otin, 2000). MMP-26 expression was restricted to epithelial cells of the endometrium (Park et al., 2002), while a very restricted expression pattern was also observed for MMP-7 with mRNA transcripts detected in the endometrium (Wilson and Matrisian, 1996). Expression of MMP-7 in uterus during the estrous cycle in rodents has been reported being most abundant at estrus and proestrus (Rudolph-Owens et al., 1997; Woessner, 1996). In our study, the expression pattern of MMP-26 in mouse uterus during the estrous cycle was similar to that of MMP-7. Therefore, the expression pattern of MMP-26 in the uterus and its structural analogy to MMP-7 suggested that MMP-26 may participate in remodeling of ECM during the estrous cycle by acting in concert with other enzymes. MMP-26 is reported to be self-activated, and cleave fibrinogen and ECM proteins (De Coignac et al., 2000; Park et al., 2000, 2002; Marchenko et al., 2001). MMP-26 can also be able to activate pro-MMP9(Uria and Lopez-Otin, 2000). Studies indicated that MMP-9 was expressed throughout the menstrual cycle and had its highest expression in glandular cells during the mid-secretory phase (Skinner et al., 1999; Hickey et al., 2001). Furthermore, MMP-9 was also one of the key regulators of ECM degradation during implantation (Behrendtsen et al., 1992; Whiteside et al., 2001). MMP-26 may play a key role in

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Acknowledgements

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endometrial tissue organization throughout the menstrual cycle, including ECM turnover and angiogenesis (Park et al., 2000, 2002; Uria and Lopez-Otin, 2000; De Coignac et al., 2000; Marchenko et al., 2001). Therefore, it could be deduced that MMP-26 may influence endometrial tissue turnover, directly or indirectly by activating pro-MMP-9. In conclusion, the restrict expression pattern of MMP-26 mRNA in mouse uterus during the estrous cycle and early pregnancy suggested that MMP-26 may participate in the cyclic changes of the uterus.

This study was supported by the Special Funds for Major State Basic Research Project (G1999055903), the Knowledge Innovation Project of the Chinese Academy of Sciences (KSCX3IOZ-07), the Florida State University Developing Scholar Award (to Q.-X. S.) and FSU Research Foundation Program Enhancement Grants (to Y.-G. Z. and Q.-X. S.). References

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