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J Dent Res 81(4): 241-246, 2002
© 2002 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Matrilysin (Matrix Metalloproteinase-7) Expression in Human Junctional Epithelium

V.-J. Uitto1,2,*, J.I. Salonen3, J.D. Firth1, H. Jousimies-Somer4, and U. Saarialho-Kere5

1 Department of Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, 2199 Wesbrook mall, Vancouver, BC, V6T 1Z3, Canada;
2 Department of Oral and Maxillofacial Diseases, Surgical Hospital, HUCH, Helsinki, Finland;
3 Turku Centre for Biomaterials, University of Turku, FIN-20520, Turku, Finland;
4 National Public Health Institute, Anaerobe Reference Laboratory, FIN-00300 Finland; and
5 Department of Dermatology, Helsinki University Central Hospital, Meilahdentie 2, FIN-00250 Helsinki, Finland;

*corresponding author, jukka.uitto{at}helsinki.fi


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Matrilysin is a matrix metalloproteinase expressed in exocrine and mucosal epithelium in many human tissues. Immunohistochemical staining showed that matrilysin is expressed in suprabasal cells of junctional epithelium facing the teeth and in epithelial cell rests of Malassez. No matrilysin expression was seen in the periodontal pocket tissue. In a tissue culture model mimicking junctional epithelium, matrilysin expression was also observed in suprabasal epithelial cells. Of 13 anaerobic oral bacterial species tested, F. nucleatum, F. necrophorum, P. endodontalis, and P. denticola stimulated matrilysin expression in porcine periodontal ligament epithelial cells from 2.5- to 5.7-fold, compared with untreated cells. The enzyme was localized in intracytoplasmic vesicles that also reacted with antibodies against lysosomal membrane protein h-lamp-1. The results indicate that matrilysin may play an important role in the normal physiology of junctional epithelium.

KEY WORDS: matrilysin • matrix metalloproteinase • human gingiva • epithelial cell • Fusobacterium spp. • lysosomal membrane protein-1 • {alpha}-defensin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Matrix metalloproteinases (MMPs) form a large family of homologous neutral proteinases that have specific roles in organ development and morphogenesis, and in normal tissue turnover, cell migration, defense, and repair (Birkedal-Hansen et al., 1993; Mäkelä et al., 1999; Parks, 1999). Matrilysin (MMP-7) is the smallest of the known MMPs, with a broad spectrum of substrates. It can degrade fibronectin, laminin, type IV collagen, gelatin, elastin, entactin, tenascin, and proteoglycan core proteins. The enzyme is seldom if ever produced by resident connective tissue cells, but it is expressed constitutively in many adult epithelial cells, most notably in the glandular epithelium of the skin, lungs, reproductive organs, and salivary glands (Saarialho-Kere et al., 1995; Wilson and Matrisian, 1996). Matrilysin is involved in mucosal repair of the respiratory epithelium and cornea (Dunsmore et al., 1998; Lu et al., 1999). Matrilysin expression is linked to epithelial cell transformation. As a consequence, the enzyme probably has a significant role in the development of tumors, including adenomas and carcinomas of the breast, colon, prostate, stomach, and skin (Kähäri and Saarialho-Kere, 1999). In normal murine small intestine, specialized defense cells termed Paneth cells co-express matrilysin in the base of the epithelial folds (crypts) with {alpha}-defensins (cryptdins) (Wilson et al., 1999). Here, matrilysin converts latent cryptdin precursors into active antimicrobial peptides and is thus believed to be involved in the antimicrobial defense system of mucosa. Some microbes of normal intestinal flora and common enteric urinary track pathogens potently induce expression and activation of matrilysin in epithelial cells (Lopez-Boado et al., 2000). Because many mucosal tissues that are innately challenged by bacteria express matrilysin, we studied its expression in human gingiva.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Samples
The research was carried out according to the provisions of the Declaration of Helsinki. Periodontal tissue biopsies were taken as described earlier (Schroeder and Listgarten, 1971), with the informed consent of the patients, in accordance with the standards of the Ethical Committees of the University of Turku, Finland, and the University of British Columbia. We obtained clinically healthy periodontal specimens by extracting upper premolars, for orthodontic reasons, along with attached gingiva, periodontal ligament, and alveolar bone from a 15-year-old girl. Eight gingival biopsies composed of chronically inflamed connective tissue and pocket epithelium were obtained from routine periodontal flap surgery of patients with advanced adult-type periodontitis. All the specimens were fixed in neutral buffered formalin for 24 hrs and embedded in paraffin.

Bacterial Cultures
Both clinical isolates and ATCC bacterial strains were tested in this study (TableGo). Bacteria were isolated and identified, and samples were prepared at the National Public Health Institute, Anaerobic Reference Laboratory, Finland, according to established culture methods for each species (Holdeman et al., 1977; Jousimies-Somer et al., 1995). After being cultured, the bacteria were washed twice with sterile PBS and stored frozen in PBS. Bacterial stocks were prepared by adjustment of the OD600 to 0.5 with PBS. An aliquot of the stock solution containing partially lysed bacteria was added to epithelial cell culture medium at 1:20 and 1:100 volumes. The experiments to study the matrilysin expression were repeated at least once with each bacterial strain.


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  		Table. Bacteria and Their Sources Used in the Study.
 
Cell Culture
Porcine periodontal ligament epithelial cells (PLE) were isolated from the cell rests of Malassez as previously described (Brunette et al., 1976; Pan et al., 1995) and cultured in {alpha}-minimal essential medium ({alpha}-MEM; StemCell Technologies Inc., Vancouver, BC, Canada) supplemented with 15% fetal calf serum (Flow Laboratories, McLean, VA, USA), 100 IU/mL penicillin G, 50 µg/mL gentamycin, and 50 ng/mL amphotericin B (Gibco, Grand Island, NY, USA). Epithelial cells were allowed to grow to about 75% confluence and then were maintained in the absence of serum for 48 hrs. Thereafter, the cells were incubated with various bacteria for 24 hrs. The culture media were analyzed for matrix metalloproteinases by means of gelatin zymography as described earlier (Mäkelä et al., 1999; Uitto et al., 1998). After the cultures, epithelial cells exposed to some bacteria showed morphological changes, such as slight rounding, but their viability was not markedly altered, as assayed by the CellTiter96 assay system, which is based on the conversion of a tetrazolium salt into a formazan product in cells cultured on 96-well plates. The formazan absorbance read with an ELISA reader is directly proportional to the number of living cells in culture (Promega, Madison, WI, USA).

Oral Mucosal Explant Culture Model of Junctional Epithelium
Normal masticatory mucosa was obtained from the hard palate of a subject (age 14 yrs) undergoing an operative liberation of an unerupted maxillary canine for orthodontic reasons. The tissue was cut perpendicularly to the oral epithelium into 1 x 1 x 2 mm pieces that were placed on Millipore filter (HAWP, pore size 0.45 µm) so that, initially, epithelium and connective tissue were in contact with the substratum. The mucosal samples were cultured for 5 days in a Trowell-type tissue culture system as described by Salonen and Santti (1985). The specimens were then formalin-fixed and paraffin-embedded for immunohistochemical analysis.

Immunochemistry
We immunostained the samples utilizing an affinity-purified polyclonal anti-human matrilysin antibody, and the peroxidase-antiperoxidase technique with diaminobenzidine as chromogenic substrate and Harris hematoxylin as counterstain, as described earlier (Saarialho-Kere et al., 1993). Specificity of the matrilysin antibody has been confirmed earlier (Saarialho-Kere et al., 1993, 1995; Lopez-Boado et al., 2000). The antibody was incubated with the deparaffinized 5-µm sections for 20 hrs. Sections incubated with rabbit or mouse pre-immune serum served as controls. For immunolocalization of matrilysin, PLE cells were plated on glow-discharged glass coverslips at semiconfluent density. Cells were allowed to attach overnight in {alpha}-MEM supplemented with 10% fetal bovine serum, then were switched to serum-free media for 8 hrs. Various bacterial strains from frozen stocks were added to cultures for an additional 24 hrs. Cell cultures were processed for immunostaining by fixation in PBS containing 4% paraformaldehyde and 5% sucrose, followed by permeabilization in 0.5% Triton-X100 for 4 min and blocking in PBS containing 30 mg/mL BSA and 1 mg/mL glycine. PLE cultures were incubated with a 1:200 dilution of anti-matrilysin primary antibody, and in separate experiments also with primary antibodies to vinculin (an anti-human monoclonal antibody, Sigma, St. Louis, MO, USA), paxillin (an anti-human monoclonal antibody, Sigma), integrin ß4 (an anti-human mouse monoclonal antibody AA3, a gift from Dr. Vito Quaranta, the Scripps Research Institute), or lysosomal membrane protein-1 (an anti-human mouse monoclonal h-lamp-1 antibody, Development Studies Hybridoma Bank, Iowa State University, Ames, IA, USA) overnight at 4°C in block solution. Primary antibodies were washed 5 times with PBS containing 1 mg/mL BSA, and incubated with 1:50 fluorescent secondary antibodies Alexa 488 and Alexa-546 (Molecular Probes, Eugene, OR, USA) for 1 hr. Cultures were washed twice with PBS and viewed under confocal laser scanning fluorescent microscopy (BioRad, Hercules, CA, USA).

Northern Blot Analysis
Expression of matrilysin in bacteria-treated porcine periodontal ligament epithelial cells was measured as follows. Total cellular RNA was isolated from cultured cells by the single-step method (Chomczynski and Sacchi, 1987). Northern blot hybridization was performed as described previously (Thomas, 1983) with cDNAs labeled with [{alpha}32P]dCTP (Amersham, Inc.) by random priming. An 800-bp human matrilysin cDNA in plasmid vectors was used as the probe. A rat cDNA for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Forth et al., 1985) was used to indicate the proportional quantities of cellular RNA loaded to the gels. [32P]cDNA/mRNA hybrids were visualized by autoradiography, and the mRNA levels were quantitated by optical densitometry with the use of NIH Image software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Matrilysin is Expressed in Junctional Epithelium and in the Epithelial Cell Rests of Malassez of the Human Periodontium.
By immunostaining, matrilysin protein was found in the suprabasal cells of clinically healthy junctional epithelium facing the tooth (Fig. 1AGo) and in the epithelial cell rests of Malassez (Fig. 1CGo). There was no reaction for anti-matrilysin antibody in periodontal pocket epithelium or in any underlying connective tissue (Figs. 1E, 1FGoGo). To study if matrilysin is expressed in the total absence of infection and inflammation, we used an explant model of human junctional epithelium. Matrilysin antibody reacted with the suprabasal layers of the epithelium, mimicking junctional epithelium (Figs. 1B, 1DGoGo). There was no reaction with the epithelial cells that had migrated on connective tissue on the dorsal surface of the explants (Fig. 1BGo). Similarly, matrilysin was not detected in the oral gingival epithelium in vivo or in resident connective tissue cells in any samples. The results suggest that matrilysin is constitutively expressed in junctional epithelium.



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  		Figure 1. Matrilysin (MMP-7) expression in epithelium of human periodontium. Histological sections were prepared from normal periodontal tissue obtained during therapeutic removal of tooth 24 (A and C) and from a palatal explant tissue cultured on a Millipore filter for 5 days (B and D). Positive reaction with anti-matrilysin antibody (brown, indicated by arrows) can be observed in junctional epithelial cells facing the tooth (A) and in epithelial cell rests of Malassez (C). Suprabasal cells of the explant epibolus at the filter side also reacted with the anti-matrilysin antibody (B; a higher magnification in D). No reaction was detected in connective tissue (CT) in either the gingival tissue or the explant. Neither pocket epithelium (PE) nor infiltrated connective tissue (ICT) of periodontal pocket tissue reacted with matrilysin antibody (E and F).

 
Matrilysin is Expressed in Cultured Epithelial Cells Exposed to Oral Bacteria.
Because we found that the epithelial cell rests of Malassez express matrilysin in vivo, we assessed if these cells can be stimulated to produce the enzyme when exposed to oral bacteria in culture. Northern analysis showed that, in uninfected porcine periodontal ligament epithelial cells (PLE cells), matrilysin expression was very low. However, the following bacteria significantly (Student's t test, p < 0.01) increased matrilysin expression compared with untreated control cells: F. nucleatum, 2.8 ± 0.7-fold; F. necrophorum, 5.6 ± 0.9-fold; P. endodontalis, 3.5 ± 0.8-fold; and P. denticola, 4.2 ± 1.5 (Fig. 2Go). P. gingivalis, P. buccae, P. oris, P. intermedia, P. nigrescens, P. loescheii, A. actinomycetemcomitans, M. dentalis, or C. rectus did not increase matrilysin expression. Semiconfluent epithelial cell cultures infected with F. necrophorum or F. nucleatum were studied for the cellular localization of matrilysin by immunofluorescent confocal microscopy. Faint signal for matrilysin was localized around the nucleus in unstimulated PLE cells. In the infected cultures, the enzyme was found in vesicular structures, mostly perinuclearly, in the cytoplasm of some but not all epithelial cells (Fig. 3DGo). Double-labeling experiments revealed colocalization between bacteria-induced expression of matrilysin and lysosomal membrane protein h-lamp-1 throughout the height of the infected cells (Figs. 3B, 3D, 3FGoGoGo). These structures were also seen in smaller amounts in untreated epithelial cells, but their matrilysin content was evident only in cells exposed to the bacteria.



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  		Figure 2. Up-regulation of matrilysin expression in epithelial cells cultured in the presence of oral bacteria. Bacteria (a stock solution, OD600 = 0.5) were added at a 1:50 dilution to semiconfluent porcine periodontal ligament epithelial cell cultures. After 24-hour culture in the absence of serum, total RNA (20 µg/sample) isolated from the cells was analyzed by Northern hybridization, with specific cDNA probes for human matrilysin and glyceraldehyde-3-phosphate dehydrogenase (GAPD; a loading control). The expression levels of matrilysin were quantified by densitometric scanning (bar graph).

 


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  		Figure 3. Bacterially induced matrilysin expression colocalizes with lysosomal structures in cultured epithelial cells. Untreated control (A, C, E) and F. necrophorum (AHN 12454)-treated (B, D, F) periodontal ligament epithelial cells were simultaneously immunostained for matrilysin and lysosomal membrane protein h-lamp-1, followed by two fluorescent secondary antibodies Alexa-488 and Alexa-546. Samples were analyzed by laser confocal microscopy, and optical z-axis sections were recorded. Optical sections—one each from the basal, middle, and apical regions of the cells—were presented together. Red channel (A, B), corresponding to Alexa-546 fluorescence, reveals h-lamp-1 expression, and green channel (C, D), corresponding to Alexa-488 fluorescence, reveals matrilysin expression. Red and green images were merged into an RGB file (E, F) showing colocalization (yellow) of the two signals.

 
Gelatin zymography of the culture medium of the F. necrophorum-treated PLE cells showed increased secretion of MMP-9 and proteinases of 40 and 50 kDa but only a weakly detectable band at 30 kDa, corresponding to the molecular size of promatrilysin (Fig. 4Go). Matrilysin was also not detected by Western blot analysis of the media samples (not shown).



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  		Figure 4. Matrix metalloproteinase (MMP) secretion of F. necrophorum-treated epithelial cells. Confluent cultures of porcine periodontal ligament epithelial cells were exposed to F. necrophorum (AHN 12454) for 20 hrs. Untreated cells served as control. Medium aliquots of 25 µL were analyzed for matrix metalloproteinases, by means of gelatin zymography. Known molecular sizes of proMMP-9, -2, and –7 are indicated.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In physiological situations, matrilysin expression in humans is limited to the secretory and ductal epithelium of various exocrine glands, suggesting that it has a specialized function in mucosal and glandular tissues (Saarialho-Kere et al., 1995; Wilson and Matrisian, 1996; Dunsmore et al., 1998). We report here that matrilysin is expressed in the suprabasal cells of junctional epithelium next to the internal basal lamina. Even though the samples were collected from clinically healthy periodontal sites, it was not possible to know if the enzyme is also expressed in strictly healthy gingiva unchallenged by bacteria. We therefore used an oral mucosal explant model of junctional epithelium. The epithelium that forms between connective tissue of the explant and the substrate on which it grows shows the same cytokeratin profile and attachment characteristics as the junctional epithelium in vivo (Salonen and Santti, 1985; Salonen et al., 1989). The results suggest that the suprabasal cells of junctional epithelium at the internal basal lamina side express matrilysin constitutively. These cells express a phenotype of relatively weak intercellular adhesion and are suggested to represent the migratory cell population of the junctional epithelium (Salonen et al., 1989). Matrilysin expression, therefore, may have a specific function in the intra-epithelial cell migration process in this rapidly renewing epithelium. The enzyme could cleave the pericellular or cell-surface proteins or {alpha}6ß4 integrin, which is a major cell receptor of hemidesmosomes binding to laminin-5 in the internal basal lamina of junctional epithelium (Hormia et al., 1992; Thorup et al., 1997; von Bredow et al., 1997).

Another role of matrilysin in the junctional epithelium may be association with the antimicrobial defense. To resist the constant challenge of oral bacteria, this epithelium must have potent antimicrobial mechanisms. Our study showed that porcine periodontal ligament epithelial cells are able to express matrilysin in culture when stimulated with certain bacteria. Non-cornified epithelial cells from the colon, bladder, and trachea, and intact mucosal epithelial tissues have a strong matrilysin response to some bacteria (Lopez-Boado et al., 2000). Epithelial cell rests of Malassez and junctional epithelial cells are cytokeratin-19-expressing non-keratinizing epithelial cells with limited differentiation potential (Dale et al., 1990). PLE cells derived from Malassez cell rests retain this phenotype in culture condition (Pan et al., 1995). It seems that the differentiation status is a factor in the matrilysin expression in epithelial cells. Analogously, we have found that another MMP, collagenase-3, is also produced by activated PLE cells but not by keratinocytes in culture (Uitto et al., 1998). In cultured PLE cells, the synthesized matrilysin localized in lysosome-like vesicles, as indicated by double-staining with lysosomal membrane protein-1 antibody. The enzyme was not found in the culture medium, suggesting that it is used for intracellular function or may be bound to cell-surface or pericellular matrix. It is interesting that only certain oral bacterial species, most notably F. necrophorum, F. nucleatum, and P. denticola, were able to stimulate matrilysin expression. All these species are opportunistic pathogens. They are found in healthy oral cavities of both children and adults, but their number is markedly increased in oro-pharyngeal diseases such as dental and mucosal abscesses, periodontitis, necrotizing stomatitis, and tonsillitis (Jousimies-Somer et al., 1993; Moore and Moore, 1994; Falkler et al., 1999; Könönen, 2000). Some well-known oral pathogens, such as P. gingivalis and A. actinomycetemcomitans, did not induce the enzyme. Therefore, it is unlikely that the factor causing the induction is a general structural molecule such as lipopolysaccharide. In fact, lipopolysaccharide from several E. coli strains does not induce matrilysin in cultured carcinoma cells (Lopez-Boado et al., 2000). The bacteria stimulating matrilysin expression appear to have a specific interaction with epithelial cells. F. nucleatum has been shown to adhere to and invade epithelial cells in vitro through a lectin-like interaction. Consequently, F. nucleatum activates signal transduction pathways and IL-8 secretion in the infected cells (Han et al., 2000).

The role of matrilysin in junctional epithelium is so far unclear. Even though matrilysin itself does not possess antimicrobial activity, it can convert antibacterial {alpha}-defensin peptides to their active forms by cleaving an anionic NH2-terminal propeptide (Wilson et al., 1999). Defensins are cationic peptides produced by several vertebrate cell types, most notably neutrophils and epithelial cells, and they play an important part in the antimicrobial defense of the body (Ganz and Weiss, 1997). Beta-defensins-1 and -2 have been detected in human gingival epithelium (Krisanaprakornkit et al., 1998, 2000). Their expression is stimulated by some commensal oral bacteria such as F. nucleatum. Possibly, junctional epithelium has an antimicrobial defense mechanism similar to that of other mucosal tissues exposed to bacteria, such as the lungs and intestine. Matrilysin may also control inflammatory reaction in junctional epithelium by cleaving cell-surface and matrix proteins or proteoglycans, thereby creating bioactive substances. However, when detached from the tooth surface and converted to pocket epithelium, junctional epithelium appears to lose its ability to produce matrilysin, and possibly some of its defense functions.


   ACKNOWLEDGMENTS
 
The authors thank Dr. William Parks for his valuable comments on the manuscript. The expert technical assistance of Arja Kanervo, BS, is highly appreciated. The study has been supported by grants from CIHR, Canada, the Academy of Finland, and the Sigrid Juselius Foundation.

Received August 22, 2000; Last revision December 17, 2001; Accepted February 6, 2002


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 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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