Molecular Human Reproduction, Vol. 9, No. 4, 205-211,
April 2003
© 2003 European Society of Human Reproduction and Embryology
Article |
Matrix metalloproteinase-28 transcript and protein are expressed in rhesus monkey placenta during early pregnancy
Submitted on October 26, 2002; accepted on January 6, 2003
1 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuan Xilu, Haidian District, Beijing 100080, P.R. China and 2 Departments of Pathology and Virology, Haartman Institute and Biomedicum Helsinki, University of Helsinki and Helsinki University Hospital, FIN-00014, Helsinki, Finland
3 To whom correspondence should be addressed. e-mail: zhuc{at}panda.ioz.ac.cn
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ABSTRACT |
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The role of matrix metalloproteinases (MMP), especially newly described MMP, in trophoblast invasion during human embryo implantation is poorly understood. In this report, using a model of early pregnancy in the rhesus monkey, we have examined the expression and localization of the most recently identified MMP, MMP-28/epilysin, transcript and protein in macaque uterine samples on days 12, 18 and 26 of pregnancy. MMP-28 mRNA expression was shown by in-situ hybridization after day 12 of pregnancy, and both the syncytial and the cytotrophoblastic cell layers of placental villi, the cytotrophoblast cells of the trophoblastic column, and the extravillous trophoblast cells of trophoblastic shell were primary producers of MMP-28 transcript. Expression of MMP-28 mRNA was undetectable in the endovascular trophoblast cells, decidual cells, luminal and glandular epithelium, arterioles, and myometrium. RT–PCR analysis amplified a fragment of 258 nucleotides from rhesus monkey uterine samples containing implantation sites on days 18 and 26. The cDNA fragment, following sequencing, was confirmed to be part of the haemopexin-like domain of MMP-28. It has 95% identity with the corresponding region of human MMP-28 gene. Immunohistochemical analysis further demonstrated that the localization of MMP-28 protein was similar to that of its mRNA. The restricted distribution pattern of this novel MMP in the villous and extravillous trophoblasts during rhesus monkey early pregnancy suggests a potential role in trophoblast invasion associated with embryo implantation.
Key words: early development/implantation/placenta/pregnancy/uterus
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Introduction |
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Matrix metalloproteinases (MMP) together with their tissue inhibitors (TIMP) participate in the extracellular matrix (ECM) remodelling in both physiological and pathological processes (Rudolph-Owen et al., 1998; Woessner, 1999; Uria and Lopez-Otin, 2000; Vu and Werb, 2000; Curry and Osteen, 2001; Coussens et al., 2002). Mammalian embryo implantation is a very complex and highly regulated process involving extensive remodelling of endometrial ECM to accommodate the embryo with invasive trophoblasts. Although new members of the MMP family are continuously emerging and there are growing experimental data that suggest MMP are important proteolytic enzymes to accomplish successful implantation (Alexander et al., 1996; Das et al., 1997; Hurst and Palmay, 1999; Bischof and Campana, 2000; Sternlicht and Werb, 2001; Wang et al., 2001; Zhao et al., 2002), the role of most MMP, especially newly characterized MMP, in embryo implantation remains poorly understood.
MMP-28, or epilysin, is the most recently identified MMP which belongs to the MMP-19 subfamily of the MMP superfamily (Lohi et al., 2001; Marchenko and Strongin, 2001). In contrast to most other soluble MMP, MMP-28 has a furin activation sequence (RRKKR). Whereas most MMP genes have 10 exons, the MMP-28 gene has only eight exons, and only three of the seven splice sites are located at positions conserved among MMP genes (Lohi et al., 2001). Interestingly, MMP-28 promoter has distinctive structural and functional features: it has no TATA box or CCAAT sequences close to the transcription start site, and basal promoter activity depends on a GT-box sequence that is able to bind transcription factors of the Sp family (Illman et al., 2001). We have previously shown by Northern blot analysis that MMP-28 mRNA is expressed in human placenta (Lohi et al., 2001). This suggests a possible role for this novel protease in the tissue remodelling processes in placenta. The detailed expression pattern of MMP-28 in placenta and uterus and its role in embryo implantation are unclear at present. As a first step towards understanding the potential role of MMP-28 in primate embryo implantation, we evaluated the distribution pattern of MMP-28 transcript and protein in rhesus monkey placenta and uterus during early pregnancy by in-situ hybridization, RT–PCR and immunohistochemistry.
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Materials and methods |
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Animals and tissue collection
Rhesus monkeys (Macaca mulatta) were obtained from the Center for Medical Primates, Institute of Medical Biology, Chinese Academy of Medical Sciences, Beijing. All experimental protocols were approved by the ethical committee of the State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences. Female rhesus monkeys (n = 12) with regular menstrual cycles and histories of pregnancy were chosen for this experiment. Pregnancy prediction and dating, and tissue recovery were conducted as detailed elsewhere (Wang et al., 2001). Briefly, the uteri were removed from at least two animals at each time point on days 12, 18 and 26 of pregnancy. The uterine sample containing the implantation site was divided into two parts, with one part for in-situ hybridization analysis and the other for RNA extraction. RNA was also extracted from the uterine samples which did not contain an implantation site.
Probe labelling
Briefly, a 307 base pair (bp) fragment encompassing nucleotides (nt) 276 to 582 of the human MMP-28 sequence (GenBank accession no. AF219624; Lohi et al., 2001) was cloned and inserted into a pGEM®-T Easy vector (Promega, USA) to prepare hybridization probes. To generate an antisense probe, the plasmid was linearized with Nco I and transcribed in vitro with SP6 RNA polymerase (Promega); the sense probe was synthesized using Sal I and T7 RNA polymerase (Promega). The probes were labelled with digoxigenin (DIG) RNA labeling mix (Roche Molecular Biochemicals, Germany) according to the manufacturer’s instructions.
In-situ hybridization
The in-situ hybridization protocol was a modification of that of Braissant and Wahli (1998) and was detailed previously (Li et al., 2002). Visualization of the hybridization signal was performed with nitroblue tetrazolium (NBT) and 5-bromo-4-chloro-3-indolyl phosphate (BCIP) in substrate buffer (100 mmol/l Tris, 100 mmol/l NaCl, 50 mmol/l MgCl2, pH 9.5). Non-specific staining was removed by rinsing the slides in 95% ethanol for 1 h. Negative controls were parallel sections hybridized with sense probes. The results were based on careful comparison between the signals of anti-sense probes and those of sense probes. Digital images were taken by SPOT system (Diagnostic Instruments, Inc., USA).
RNA isolation
Total RNA was extracted with Trizol reagent (Gibco BRL, USA) according to the manufacturer’s instructions. RNA integrity was determined by agarose– formaldehyde gel electrophoresis by examination of the intensity of the 28 S and 18 S bands. RNA yields were quantified by UV spectrophotometry at 260 nm, and RNA samples were kept at –80°C until used.
RT–PCR
Oligonucleotide primers were designed and synthesized based on the published cDNA sequence of human MMP-28 (GenBank accession no. AF219624) with an expected product of 258 bp. The primers were 5'-CAAGCCAGTGTGGGGTCT-3' (sense) and 5'-TAGCGGTCATCTCGGAAG-3' (antisense). The sense primer encompasses nt 1366–1383, whereas the antisense primer corresponds to nt 1606–1623 of the human MMP-28 sequence. Reverse transcription was carried out in a DNA thermal cycler (Gene Amp PCR system 2400; Perkin–Elmer, USA). Total RNA (2 µg) was reverse-transcribed using reverse transcriptase (Superscript II; Gibco BRL) and an oligo dT-primer in a 20 µl volume, according to the manufacturer’s instructions. The reaction was performed at 42°C for 50 min, and inactivated at 70°C for 10 min.
Amplification of the MMP-28 gene was performed in a 25 µl mixture containing 2 µl of reverse transcription products, 2 mmol/l of MgCl2, 200 µmol/l of dNTP, 10 pmol of each MMP-28 primer, and 1 IU of Taq DNA polymerase. The PCR was run for 28 cycles (denaturing at 95°C for 45 s, annealing at 55°C for 45 s, and elongating at 72°C for 45 s) followed by an extra 7 min at 72°C. Amplification of a 548 bp ß-actin gene using specific primers (Li et al., 2002) was also performed to confirm the efficacy of the system. Parallel controls in which RNA or reverse transcriptase was omitted were included to exclude possible DNA contamination. The PCR products were visualized under UV light on 1% agarose gels containing ethidium bromide.
Cloning and sequencing of the rhesus monkey MMP-28 partial cDNA
The amplified MMP-28 cDNA fragment with the expected size was recovered and purified using CONCERTTM Rapid Gel Extraction system (Gibco BRL). The cDNA was cloned into pGEM®-T Easy vector (Promega), and sequenced from three different clones to exclude mutations generated by Taq polymerase. The sequencing was performed commercially (Sangon Corp., China) by using an Applied Biosystems Automated sequencer, ABI PRISM 377–96 (Perkin–Elmer).
Immunohistochemistry
Polyclonal antibodies against human MMP-28 raised in rabbits were prepared and purified in our previous work. The specificity of the antibody to recognize MMP-28 has been demonstrated in previous Western blot analysis studies (Lohi et al., 2001). Immunohistochemistry was carried out with a Vectastain ABC kit (Vector Labs, USA) as detailed elsewhere (Li et al., 2002). Primary antibodies included affinity-purified rabbit anti-human MMP-28 antibody [1 µg/ml in phosphate-buffered saline (PBS)–0.3% bovine serum albumin (BSA)], mouse anti-vimentin antibody, mouse anti-cytokeratin antibody, and mouse anti-actin antibody (4 µg/ml in PBS–0.3% BSA; Santa Cruz Biotechnology Inc., USA). Biotinylated anti-rabbit or anti-mouse IgG was used as secondary antibody. Colour reaction was performed with a diaminobenzidine (DAB) kit (Zhongshan Corp., China). The staining specificity of MMP-28 antibody was confirmed by incubating parallel sections with antibodies that had been previously blocked with 400-fold molar excess of MMP-28 immunogenic peptide. Negative controls were also included in which the primary or secondary antibody was omitted.
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Results |
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In-situ localization of MMP-28 mRNA in the macaque placenta during early pregnancy
As demonstrated in Figure 1, the placental villi on days 18 (Figure 1A) and 26 (Figure 1B) of pregnancy showed strong hybridization signals for MMP-28 antisense probe. Observation at a higher magnification revealed that MMP-28 mRNA was localized in both the syncytial and the cytotrophoblastic cell layers of placental villi (Figure 1E), and the cytotrophoblasts of the trophoblastic column (Figure 1D). No staining was observed on day 12 of pregnancy (data not shown). Sense RNA probes for MMP-28 did not generate specific hybridization signals above background level (Figure 1C). The decidua and placental villi were identified by immunohistochemical localization of vimentin and cytokeratin, as representatively shown in Figure 1F and G. Villous mesenchyme and decidual cells are anti-vimentin reactive, whereas syncytiotrophoblasts and cytotrophoblasts are immunoreactive with anti-cytokeratin antibody.
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In addition to its predominant placental villi distribution, MMP-28 mRNA was also expressed in the extravillous trophoblast cells of the trophoblastic shell on day 26 of pregnancy (Figure 2A). To further explore if endovascular trophoblast cells are capable of synthesizing MMP-28 mRNA, cytokeratin antibodies were used as markers to distinguish the extravillous trophoblast cells in the maternal tissue (Figure 2D), while anti-actin antibody was applied to stain arterioles (Figure 2C). No specific staining was observed in the uterine arterioles of any of the samples examined at any of the time points as demonstrated in Figure 2B. No staining in other extravillous trophoblast cells in the decidua was visualized either (data not shown). Expression of MMP-28 mRNA was also undetectable in decidual cells (Figure 2A), luminal and glandular epithelium, and myometrium at all the time points examined (data not shown).
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RT–PCR analysis of MMP-28 mRNA transcription in rhesus monkey
To confirm transcription of MMP-28 during macaque early pregnancy, RT–PCR analysis was carried out in the presence of human MMP-28 primers. As shown in Figure 3, a band of 258 bp in size was obtained from the monkey uterine samples containing implantation sites on days 18 and 26, but no specific band was visualized on day 12. A clear band of ß-actin was amplified from each sample at the three time points. Negative controls which lacked cDNA in the PCR system (data not shown) and the controls of uterine samples with no implantation sites did not show specific amplification.
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Identification of the partial sequence of MMP-28
The identity of the MMP-28 PCR products was confirmed by sequencing, and the cDNA sequence (GenBank accession no. AY145891) is shown in Figure 4A. This partial cDNA fragment has 95% sequence identity with the corresponding region of human MMP-28 gene (nt 1366 to 1623, GenBank accession no. AF219624). The nucleotide sequence encodes monkey MMP-28 protein fragment corresponding to the human MMP-28 protein sequence between Lys400 and Tyr485 (GenBank protein_id = ‘AAK01480.1’). Based on the human MMP-28 protein structure, the deduced monkey protein fragment represents part of the haemopexin-like domain. Only two amino acid differences—His/Arg416 and Gly/Arg443—exist between the monkey (amino acids 1–86) and human (amino acids 400–485) protein sequences (Figure 4B).
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Immunohistochemical localization of MMP-28 protein in rhesus monkey placenta during early pregnancy
To further identify MMP-28 protein synthesis in the rhesus monkey placenta and uterus during early pregnancy, immunohistochemical analysis was performed in this study. The results showed that the localization of MMP-28 protein was similar to that of its mRNA at the three time points. As shown in Figure 5, strong MMP-28 immunostaining was visualized in the syncytial and the cytotrophoblastic cell layers of placental villi (Figure 5A, C), the cytotrophoblast cells of the trophoblastic column (Figure 5D), and the extravillous trophoblast cells of trophoblastic shell (Figure 5A). MMP-28 protein was not detected in the endometrial epithelial glands (Figure 5E), the stroma component (Figure 5E, F), and the arteriole of the maternal tissue (Figure 5F). Luminal epithelium and myometrium of the uterus were also negative for this antigen (data not shown). Control sections which had been incubated with the antibody that had been pre-absorbed with MMP-28 blocking peptide did not show specific immunostaining (Figure 5B). The staining signal was also absent in the negative control sections in which the primary or secondary antibody was omitted (data not shown).
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Discussion |
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Little is known about the role of proteinases in trophoblast invasion during embryo implantation in the human due to the extremely limited access to early human placental specimens. Using a model of early pregnancy in the rhesus monkey which is very similar to implantation and trophoblast differentiation/invasion in the human (Enders, 1989; Feng et al., 2000), we have shown for the first time that both the transcript and protein for the novel MMP-28 were localized to the placental villi, cell column and the trophoblastic shell during early pregnancy. No expression was observed in the endometrium or myometrium during early pregnancy or throughout the estrous cycle (data not shown). This new evidence suggests a role for MMP-28 in human implantation.
Interestingly, RT–PCR identified a partial cDNA fragment corresponding to part of the MMP-28 haemopexin-like domain. As the majority of MMP share significant homology within the haemopexin-like domain, we performed Basic Local Alignment Search Tool (BLAST) analysis against the National Center for Biotechnology Information (NCBI) database. The result showed that the amplified sequence matched not only MMP-28 but also MMP-25. However, MMP-25 (MT6-MMP/leukolysin) has previously been shown to be specifically expressed by peripheral blood leukocytes among various tissues examined including placenta (Pei, 1999). Further, the RT–PCR amplification was stage-specific and the uterine samples with no implantation sites did not show specific amplification. Consequently, we believe that the amplified cDNA represents a portion of MMP-28 instead of MMP-25 or other MMP.
Although the primate placenta exhibits dramatic invasive character at early pregnancy, and expression of MMP-2, -7, -9, -11 and -14 was documented in human placenta (Fata et al., 2000), the invasion is confined spatially to the uterus and temporally to early pregnancy (Hurskainen et al., 1998). Indeed, a balance of factors regulates the invasive properties of the embryo and the anti-invasive properties of uterine decidua (Wong et al., 2002). We previously demonstrated that in the macaque placental villi, MMP-2, -9, -14 mRNA were abundantly expressed, and the trophoblastic shell was a producer of MMP-2, -14 and TIMP-3 transcripts (Wang et al., 2001). More recently, we identified another new member of the MMP family, MMP-26 (endometase/matrilysin-2), from the endometrium of early pregnant rhesus monkey and showed that its expression was highly restricted to the glandular epithelium and spiral arteries, but not in the placental compartments (Li et al., 2002). We herein extend our previous research by demonstrating that the placental villi, cell column and trophoblastic shell are capable of synthesizing significant amounts of a novel MMP, MMP-28/epilysin.
Cytotrophoblast cells derived from the blastocyst trophectodermal cells may differentiate via two pathways: villous cytotrophoblast cells form a monolayer of polarized cells that proliferate and fuse to form syncytiotrophoblasts covering the surface of the villi. Cytotrophoblast cells in the anchoring villi can also break through the syncytium to form multilayered columns of non-polarized cytotrophoblast cells (Bischof et al., 2001). The cytotrophoblasts of trophoblastic columns form the cell reservoir for new villi and anchor the embryo to the uterine wall (Hurskainen et al., 1998). The proliferation and differentiation of cytotrophoblastic cells in the cell columns are important for the development of the placenta, and may link with the ability of the trophoblast to invade. The finding of MMP-28 expression in cytotrophoblast cells of trophoblastic columns is in keeping with the evidence that human cytotrophoblasts of columns produce MMP-2, -9, -14 and their inhibitors, TIMP-1, -2 and -3 (Polette et al., 1994; Hurskainen et al., 1996, 1998). Recently, it has been suggested that MMP-28 is associated with cell proliferation via restructuring the basement membrane or degrading adhesive proteins between keratinocytes (Saarialho-Kere et al., 2002). Hence, production of MMP-28 in the trophoblastic columns may implicate an involvement of this protease in cytotrophoblast cell proliferation. More importantly, MMP-28 was not only produced by proliferating trophoblast cells in the trophoblastic columns, but also synthesized by some invasive extravillous trophoblast cells. Since the trophoblastic shell on the surface of the decidual membrane consists of invasive trophoblasts and exhibits the invasive capacity (Hurskainen et al., 1998), expression of MMP-28 in these cells may suggest its involvement in trophoblast invasion.
To accomplish a successful implantation, the extravillous trophoblast cells need to invade the uterine arterioles to create large-diameter, low-resistance and high-flow vessels (Staff et al., 2000). Therefore, MMP-28 expression might also occur in the endovascular trophoblast cells. However, both the transcript and protein for MMP-28 was undetectable in these cells. It is not surprising in consideration of the expression of other proteinases such as MMP-14 around the uterine arterioles by human intermediate trophoblasts (Hurskainen et al., 1998). Taken together, our results indicate that MMP-28 expression is restricted to certain types of trophoblast cells, and imply that coordinated expression of MMP-2, -9, -14 and -28 in the placental villi and trophoblastic shell may be important for trophoblast invasion during embryo implantation in the rhesus monkey.
In summary, we present for the first time the expression of MMP-28 gene and protein in early pregnant rhesus monkey placenta. The distinct expression profile suggests that this novel MMP may be implicated in primate embryo implantation, which is a key event in the establishment of successful pregnancy. These data add to our understanding that various MMP are involved in the complicated process of primate embryo implantation via their distinct and coordinated expressions.
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Acknowledgements |
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The authors would like to thank Prof. Ru-Jin Zou and Jie-Jie Dai for their assistance with tissue collection, and Dr Alex Y.Strongin (Burnham Institute, La Jolla, CA, USA) for kindly offering beneficial literature. We also thank Dr Qing-Xiang Amy Sang (Florida State University, Florida) for previous help on MMP research. This study was supported by the Special Funds for Major State Basic Research Project (G1999055903) and the CAS Innovation Program (KSCX3-IOZ-07).
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