Molecular Human Reproduction, Vol. 7, No. 1, 73-78,
January 2001
© 2001 European Society of Human Reproduction and Embryology
Uterine physiology |
Expression patterns of cathepsins B, H, K, L and S in the human endometrium
1 Departments of Obstetrics and Gynecology, 2 Molecular Biology and Medical Biochemistry, and 3 Pathology and MediCity Research Laboratory, University of Turku, FIN-20520 Turku, Finland
Abstract
Cathepsins B, H, K, L and S belong to the family of lysosomal cysteine proteinases and participate in a variety of proteolytic processes, including degradation of the extracellular matrix (ECM). In the present study, we used Northern hybridization to demonstrate the presence of mRNAs for cathepsins B, H, K, L and S in human endometrium during both the proliferative and secretory phases of menstrual cycle. The mRNA levels for cathepsins H and K were significantly lower in secretory phase endometrium in comparison with proliferative phase endometrium. Immunohistochemical localization of the different cathepsins revealed widespread distribution of all cathepsins in both stroma and epithelial cells. The immunoreactivity for cathepsins B, H and K exhibited changes related to endometrial location and/or to the phase of the cycle. The strongest immunoreactivity for cathepsins B, H, L and S was observed in the surface epithelium of the endometrium. The staining for cathepsins was predominantly intracellular, but immunoreactivity was also detected on the surface of small lymphoid cells in the stroma. The findings of the present study suggest that cysteine cathepsins are needed for normal development and function of human endometrium during both the proliferative and secretory phases.
cathepsin/cysteine proteinases/endometrium/extracellular matrix/human
Introduction
During the menstrual cycle, the endometrial glands and stroma undergo extensive cyclic changes including rapid growth in proliferative phase, differentiation in secretory phase and programmed breakdown during menstruation. An integral part of normal tissue growth and differentiation is remodelling of extracellular matrix (ECM) through controlled proteolysis. In the non-pregnant uterus, the best characterized components of the endometrial stroma are fibronectin and types I, III, V and VI collagen (Aplin et al., 1988
; Iwahashi et al., 1996).
At least two different groups of proteolytic enzymes, matrix metalloproteinases (MMPs) and serine proteinases have been implicated in the remodelling of the endometrial ECM (Koh et al., 1992; Rodgers et al., 1994; Salamonsen and Woolley, 1996). An alteration in the balance of MMPs and their tissue inhibitors has been shown to result in the breakdown of stromal ECM and consequently in menstruation (Hampton and Salamonsen, 1994; Salamonsen and Woolley, 1996). A relationship between increased proteinase activity and dysfunctional uterine bleeding has also been suggested (Shaw et al., 1983; Marbaix et al., 1996; Skinner et al., 1999). Moreover, proteinase activity in the endometrium has been suggested to participate in the control of trophoblast implantation (Salamonsen, 1999; Schatz et al., 1999). The activity of MMPs and serine proteases is dependent upon the phase of the menstrual cycle (Koh et al., 1992; Rodgers et al., 1994) and on steroid hormone concentrations (Marbaix et al., 1992; Rodgers et al., 1994; Casslen et al., 1995; Schatz et al., 1999), but the regulation and expression of cysteine proteinases in human endometrium is poorly understood.
Cysteine cathepsins are a family of lysosomal proteinases active in an acidic environment (Kirschke et al., 1998). They have the ability to degrade matrix molecules, including collagens, laminin, fibronectin and proteoglycans. A member of the cysteine proteinase family, cathepsin B, has been shown to activate MMPs and urokinase type plasminogen activator (uPA) (Eeckhout and Vaes, 1977; Schmitt et al., 1991; Murphy et al., 1992) and the closely-related cathepsin L has been shown to cleave pro-uPA into the active form (Schmitt et al., 1991). On the other hand, inactive precursors of these cathepsins can be activated by MMPs (Kirschke et al., 1998). Based on the interactions of cathepsins, MMPs and uPA, we propose that cysteine cathepsins also participate in endometrial remodelling during the menstrual cycle. In the present study, we studied the mRNA levels of cathepsins B, H, K, L and S and the tissue distribution of these enzymes in the proliferative and secretory phases of human endometrium.
Materials and methods
Study subjects
The study group consisted of 14 healthy, fertile volunteers. The mean age of the participants was 33 ± 4.5 years (range 24–38 years). Exclusion criteria for the study were present or past infertility, menstrual disorders, hormonal treatment within 6 weeks and hormonal or intrauterine contraception. The study design was approved by the Ethical Committee of Turku University and Turku University Central Hospital, and an informed consent form was signed by all participants.
An ultrasound examination was performed during the late proliferative phase to confirm normal endometrial and follicular development. Endometrial samples for RNA extraction were collected with a Pipelle de Cornier catheter (Prodimed, Neuilly-en-Thelle, France). Samples representing the implantation window in the mid-secretory phase (n = 14) were collected 6–9 days after the urinary LH peak, and those representing the proliferative phase (n = 9) in the subsequent cycle between period days 8–13. The samples were frozen in liquid nitrogen and stored at –70°C.
Specimens for immunohistochemical staining (n = 10) were collected from hysterectomies for benign reasons. The mean age of the patients in this group was 37 ± 3.5 years (30–44 years). The samples represented both the proliferative (n = 5) and secretory (n = 5) phases of the menstrual cycle. The secretory phase samples represented days 3–10 post-ovulation (for dating, see Dallenbach-Hellweg and Poulsen, 1985). The immunostained sections were read by two observers and the results reflect the consensus opinion on the relative staining intensities of different structures within the sections.
RNA extraction and mRNA analyses
For extraction of total RNA the frozen endometrium samples were pulverized under liquid nitrogen in a mortar and homogenized in guanidinium isothiocyanate as described previously (Chirgwin et al., 1979). Aliquots (10 µg) of total RNA were denatured with glyoxal and formamide, fractionated on 0.75% agarose gels, blotted onto nylon transfer membranes, and hybridized with [32P]-labelled cDNA inserts at 42°C for 20 h. The hybridizations and washes were performed as suggested by the supplier of the membrane (Pall BioSupport Division, Glen Cove, NY, USA). For reliable comparisons, all endometrial RNA samples were analysed on the same membrane.
Inserts of cDNA clones pHCatB-1, pHCatH-1, pHCatL-1, pHCatS-1(Söderström et al., 1999) and pHCatK-1 (Rantakokko et al., 1996) were used as probes for human cathepsin B, H, L, S and K mRNAs respectively. The bound probes were detected and quantified on a Molecular Imager phosphoimager and the signals corrected for variations in the 28S rRNA levels determined by hybridization. The data were analysed using Mann–Whitney–Wilcoxon test.
Immunohistochemistry
Formalin-fixed, paraffin-embedded samples were cut into 5 µm sections on silane-coated slides. Cathepsins B, H, K, L and S were detected with polyclonal antibodies described earlier (Söderström et al., 1999). Enzymes purified from human liver were used as antigens when raising polyclonal antibodies against cathepsins B, H and L (Barrett and Kirschke, 1981), and enzymes from human spleen were used for raising antibodies against cathepsin S (H.Kirschke, Halle, Germany). Polyclonal antibodies to cathepsin K were prepared against denaturated mouse procathepsin K (D.Brömme, New York, NY, USA). All antibodies were raised in rabbits. The bound primary antibodies were detected as brown precipitate using diaminobenzidine tetrahydrochloride and the avidin–biotin complex method following the instructions of the supplier (Vectastain ABC kit; Vector Laboratories, Burlingame, CA, USA). The sections were counterstained with haematoxylin. The specificity of the immunoreactions was controlled by omitting the primary antibody and by using preimmune serum.
Results
Northern analyses
Northern hybridization revealed the presence of cathepsin B, H, K, L and S mRNAs in all endometrial samples studied, although the levels of cathepsin S mRNA were considerably lower than those of the other cathepsins. Northern analysis also demonstrated a differential expression of cathepsin mRNAs between the proliferative and the mid-secretory phases in human endometrium (Figure 1). The results were quantified relative to 28S rRNA, which made it possible to compare mRNA levels between different phases (Figure 2). However, as the mRNA levels were calculated as relative hybridization units (with the highest mRNA/28S rRNA level given the value 1.0), the levels of different cathepsin mRNAs cannot be compared with each other. The mRNA levels for cathepsins H and K were found to be significantly decreased in the mid-secretory phase in comparison with the proliferative phase (P < 0.05 and P < 0.01 respectively; Figure 2). In contrast, the transcripts of cathepsin B increased very slightly from the proliferative to the secretory phase, but the increase was not statistically significant. The levels of cathepsin L and S mRNAs remained essentially unaltered during the menstrual cycle.
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Immunohistochemistry
Immunostaining of human endometrial samples for cathepsins B, H, K, L and S revealed widespread distribution of all cathepsins in both stromal and epithelial cells. However, a number of systematic differences were observed in the staining intensity of specific cell types (surface epithelium, glandular epithelium, stromal cells, and small lymphoid cells in the stroma) for the different cathepsins. In the endometrium basalis, the immunoreactivity for cathepsins H, K, L and S was stronger in glandular epithelium than in stroma (Figure 3B–E
), especially in the secretory phase. The staining intensity for cathepsin B did not exhibit a similar variation (Figure 3A). In the superficial layers of endometrium, the stroma tended to stain stronger than the glands for cathepsins B, H and K in the proliferative phase and for cathepsins B and H in the secretory phase (data not shown). The strongest immunoreactivity for cathepsins B, H, L and S was observed in surface epithelium of endometrium (Figure 3G, H, K and L respectively). The surface epithelium also stained positive for cathepsin K (Figure 3J) but the staining intensity exhibited marked regional variation from cell to cell.
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The staining for cathepsins was predominantly intracellular, but cathepsin B was also detected on the apical surface of epithelial cells (Figure 3A
). In surface and glandular epithelium, cathepsin H staining was predominantly localized to the apical pole of epithelial cells (Figure 3B). Small lymphoid cells exhibited both surface and cytoplasmic staining for cathepsin B (Figure 3M), H, L and S (data not shown). The results are summarized in Table I.
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Discussion
In the present study, we have shown that cathepsins B, H, K, L and S are produced in human proliferative and secretory endometrium. These cathepsins are lysosomal cysteine proteases capable of digesting matrix proteins and activating other proteases involved in matrix degradation (Kirschke et al., 1998). They may also contribute to apoptosis which is necessary for normal development (Afonso et al., 1997). The enzymes are secreted as proenzymes that are activated either autocatalytically or by MMPs or other cathepsins, and their action is controlled by small peptide inhibitors, cystatins (Kirschke et al., 1998). The apparently constitutive production of cathepsins both in growing and differentiating endometrium indicates that these enzymes may participate in the basic molecular turnover of the tissue.
The present study shows that the transcription of cathepsins K and H is down-regulated in human endometrium in the mid-secretory phase. This finding is in line with previous reports on the function of other proteases in human endometrium (Shaw et al., 1983; Rodgers et al., 1994; for review see Simón, 1996). Several proteases have been shown to be regulated by steroid hormones. The production of stromelysins, MMP-1, -2, -7 and -9 is down-regulated by progesterone in vitro (Marbaix et al., 1992; Osteen et al., 1994; Bruner et al., 1995; Irwin et al., 1996) and their production is diminished or absent in the secretory endometrium (Rodgers et al., 1994). However, conflicting reports on MMP-2 and -9 have also been published (Lockwood et al., 1998; Skinner et al., 1999). Serine protease activity is also lower in the secretory phase than at mid-cycle (Shaw et al., 1983; see Simón et al., 1996), probably as a response to progesterone (Schatz et al., 1999). In contrast, cathepsin D, an aspartic protease, is present at higher levels in secretory endometrium than in proliferative endometrium. Initially its production was thought to be stimulated by progesterone (Maudelonde et al., 1990) but a more complex regulation, possibly through growth factors, is probable (Camier et al., 1996). Studies with proteinase inhibitors suggest that the activity of cysteine proteinases is not dependent on progesterone concentrations (Irwin et al., 1996). However, cysteine cathepsins are differentially sensitive to different proteinase inhibitors (Kirschke et al., 1998). Cathepsins have also been demonstrated to exhibit cycle-dependent variation in localization and transcript levels in the mouse ovary (Oksjoki et al., 2001). Whether these changes are related to hormone concentrations is unresolved.
The parallel decline in the production of MMPs and cathepsins H and K in the secretory phase endometrium raises the question of whether there is interaction between these proteases. In several tissues cathepsins B and L have been shown to activate other proteases and in turn, procathepsins can be activated by MMPs (Kirschke et al., 1998). At present it is unknown whether cathepsin K has similar interactions. Despite these similarities in the production patterns of MMPs and some cathepsins, their function in endometrium is probably different: blocking the activity of cysteine proteinases with leupeptin or synthetic inhibitor E-64 does not inhibit the perimenstrual-like breakdown of endometrial ECM in vitro, whereas the presence of MMP inhibitors allows the stromal collagen structure and tissue integrity to be maintained (Marbaix et al., 1996).
Cathepsin B and L have been shown to be crucial for implantation in the mouse as pertubation of their activity with inhibitor E-64 leads to retarded decidualization and failure of implantation (Afonso et al., 1997). The present study shows that cathepsins B and L as well as the other cysteine cathepsins are produced also in human endometrium during the implantation window. The lack of MMPs other than MMP-2 in human secretory phase endometrium has lead to a hypothesis that differentation of endometrial stroma does not require diverse set of proteases (Rodgers et al., 1994). The results of the present study and those from animal experiments discussed above, however, suggest that cysteine proteinases are expressed during the implantation window and may well play a role in the differentation of endometrial stroma.
Apart from direct proteolytic effects on ECM, cysteine cathepsins may also exert their effects on by activating prohormones, growth factors or their receptors (Kirschke et al., 1998). For example, cathepsins B and H are capable of activating prorenin into renin (Luetscher et al., 1982) and cathepsin L of degrading epidermal growth factor (EGF) receptor (Hiwasa et al., 1988). In-vitro studies have shown that EGF increases the levels of MMPs in decidualizing stromal cells without affecting their inhibitors (Nuttall and Kennedy, 2000). EGF has also been suggested to enhance the apoptotic susceptibility of endometrial secretory epithelium (Tanaka et al., 1999). If cathepsin L possesses an inhibitory effect on EGF function in endometrium, it could help maintain circumstances favourable for normal decidualization.
In human endometrium, we detected cathepsins immunohistochemically both in stromal and epithelial cells. In an earlier study, cathepsin B expression has been observed in murine endometrial luminal and glandular epithelium, and cathepsin L expression in decidualising stroma (Afonso et al., 1997). In our study, immunoreactivity for cathepsins was localized predominantly intracellularly but in the small stromal lymphoid cells reactivity for cathepsins was also detected on the surface of cells. The intracellular localization is in agreement with the predominant function of cysteine cathepsins in an acidic environment, typically found in lysosomes. However, pericellular activity of cathepsins is also known to be physiologically important, e.g. in osteoclastic bone resorption (Saftig et al., 1998). It is currently unknown whether an analogous environment surrounds activated lymphoid cells.
According to our results, cathepsins are prominently immunolocalized in the surface epithelium, and cathepsins B and H at the apical surface of the epithelial cells. This suggests a role for these proteinases in the glandular secretion and in the uterine lumen, if secreted. Secretion of cathepsins and other lysosomal contents has been demonstrated earlier in haemotopoietic cells (Reddy et al., 1995; for review, see Andrews, 2000). Additionally, a possible role of cathepsins in cell adhesion and oestradiol-induced proliferation has been suggested by earlier experiments performed on rat endometrial cells, presumably mostly of epithelial type (Pietras and Szego, 1979). It can be proposed that secreted cathepsins might have a role in cell adhesion, e.g. in trophoblast attachment to the surface epithelium possibly by modifying the functional availability of adhesion and anti-adhesion molecules.
In conclusion, the present study demonstrates that cysteine cathepsins are produced in human endometrium. This suggests that cathepsins are needed for normal development and function of human endometrium during both proliferative and secretory phases. Parallel to the decline of MMP production in secretory phase, the production of cathepsins H and K is diminished in midsecretory phase endometrium as compared with proliferative phase. These findings warrant further investigations on the regulation of cathepsin activity and on the possible interactions of cathepsins with MMPs, ECM components and adhesion molecules in the endometrium.
Acknowledgments
The authors are grateful to Päivi Auho, Tuula Oivanen and Anu Kupiainen for expert technical assistance. Drs Heidrun Kirschke et al. and Dieter Brömme are acknowledged for providing the cathepsin antibodies. An unidentified referee is acknowledged for valuable comments and new references that gave us new insight in the possible role of cathepsins in cell adhesion. This study was financially supported by grants from the Academy of Finland (project no 37311), Sigrid Juselius Foundation and the Turku University Central Hospital (project no 13449). Sanna Oksjoki is a recipient of a training grant from Turku Graduate School of Biomedical Sciences.
Notes
4 To whom correspondence should be addressed at: Puutarhakatu 2 C 46, FIN-20100 Turku, Finland. E-mail: varpu.jokimaa{at}saunalahti.fi 
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Submitted on June 23, 2000; accepted on November 2, 2000.
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