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Interleukin-1 Enhances Type I Collagen-induced Activation of Matrix Metalloproteinase-2 in Odontogenic Keratocyst Fibroblasts

Second Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;

Correspondence: *corresponding author, yasu{at}dent.kyushu-u.ac.jp

	ABSTRACT

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Interleukin-1 (IL-1) is strongly expressed in odontogenic keratocysts. In this study, we investigated the effects of IL-1 on the activation of matrix metalloproteinase-2 (MMP-2) in the fibroblasts isolated from odontogenic keratocysts. Odontogenic keratocyst fibroblasts secreted a latent form of MMP-2 (proMMP-2) spontaneously. Type I collagen induced the activation of the proMMP-2, and recombinant human IL-1 (rhIL-1) further enhanced the type I collagen-induced activation of proMMP-2 in a dose-dependent manner. The rhIL-1-induced activation of proMMP-2 was inhibited by anti-human IL-1 antibody. A reverse-transcription/polymerase chain-reaction (RT-PCR) and Western immunoblotting demonstrated that the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) mRNA and protein was increased in the fibroblasts when the cells were cultured on type I collagen, and the expression was further enhanced by rhIL-1. Thus, IL-1 may up-regulate proMMP-2 activation by increasing the expression of MT1-MMP in the fibroblasts isolated from odontogenic keratocysts synergistically with type I collagen.

Key Words: interleukin-1a • type I collagen • matrix metalloproteinase-2 • membrane-type matrix metalloproteinases • odontogenic keratocyst

	INTRODUCTION

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The odontogenic keratocyst is characterized by a lining of parakeratinized or orthokeratinized stratified squamous epithelium, and grows to a large size by the destruction of osteoid extracellular matrices of the bone (Kramer et al., 1992). The bone resorption by the cyst is mediated by activation of osteoclast-like cells (Formigli et al., 1995) and/or biologically active collagenases (Sorsa et al., 1988). However, the precise regulatory mechanism responsible for the cyst growth has not been well-understood.

Matrix metalloproteinase (MMP)-2 is a gelatinase of the MMP family, and degrades many types of collagens such as native types IV, V, and X collagen, and denatured fibrillar types I, II, and III collagen (Docherty and Murphy, 1990). MMP-2 is secreted as an inactive zymogen (proMMP-2) like other MMPs, and the activation is required prior to working as a proteinase (Sato et al., 1994; Ohuchi et al., 1997). ProMMP-2 cannot be activated by serine proteinases such as plasmin, neutrophil elastases, and trypsin (Okada et al., 1990), but is activated by membrane-type MMPs (MT-MMPs) such as MT1-MMP, MT2-MMP, and MT3-MMP (Sato et al., 1994; Takino et al., 1995; Will and Hinzmann, 1995; Imai et al., 1997). It has been shown that MT1- and MT2-MMPs also degrade type I collagen (Hotary et al., 2000), and MT3-MMP can cleave the Gly4-Ile5 bond within the triple-helical portion of 2(I) chains (Shimada et al., 1999). These suggest that the regulation of the expression of MMP-2 and MT-MMPs should play a crucial role in bone resorption. It has been shown that, in addition to MMP-1, MMP-8, and MMP-9, MMP-2 is expressed in odontogenic jaw cyst walls (Teronen et al., 1995a,b; Kubota et al., 2000). Therefore, the regulation of the expression of MMP-2 and MT-MMPs might be important for odontogenic jaw cyst expansion in the jaw.

Interleukin-1 (IL-1) is expressed in a lining epithelium, and fibroblasts and endothelial cells in the subepithelial layers of odontogenic keratocysts (Meghji et al., 1992,1996; Kubota et al., 2001). Recently, we have shown that IL-1 increases the activation of proMMP-2 in odontogenic jaw cyst fragments in explant culture (Kubota et al., 2000). In addition, it has been reported that an extracellular matrix (ECM) activates proMMP-2 by inducing MT1-MMP expression in normal and malignant cells (Seltzer et al., 1994; Gilles et al., 1997).

In this study, we have investigated the effects of IL-1 and ECMs on MMP-2 activation in the fibroblasts isolated from odontogenic keratocysts to clarify the mechanisms of cyst growth in jaws, and demonstrated that IL-1 enhances type I collagen-induced MT1-MMP expression in the cyst fibroblasts, and increases proMMP-2 activation.

	MATERIALS & METHODS

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Cell Culture
Odontogenic keratocyst tissues were obtained from patients admitted to the Kyushu University Dental Hospital under institutionally approved protocols after informed consent was obtained. Fibroblasts were isolated from biopsied odontogenic keratocyst tissues by explant outgrowth, and cultured in Dulbecco's modified Eagle's medium (DMEM, Sigma Chemical Co., St. Louis, MO, USA) containing 10% heat-inactivated fetal calf serum and antibiotics (100 IU/mL penicillin and 100 µg/mL streptomycin) under a 95% air/5% CO₂ atmosphere at 37°C as previously described (Kubota et al., 2000). The fibroblasts were seeded on 12-well culture dishes (CORNING, IWAKI GLASS, Tokyo, Japan), and cultured to confluence. After pre-incubation with serum-free DMEM containing antibiotics for 24 hrs, the fibroblasts were incubated with various concentrations (0.01-10 nM) of recombinant human interleukin-1 (rhIL-1) for 48 hrs at 37°C in the presence or absence of a 1:2000 dilution of the anti-human IL-1 monoclonal antibody (anti-hIL-1 antibody). Both rhIL-1 and anti-hIL-1 antibody were supplied for free by Dainippon Pharmacy Co. (Osaka, Japan). The mouse thymocyte comitogenic activity (LAF) of rhIL-1 is 2.01 x 10^-7 U/mg.

The fibroblasts were homogenized in a 0.5-mL SDS sample buffer containing 1% SDS, 10 mM Tris-HCl (pH 6.8), and 10% sucrose. The supernatants of the culture media were centrifuged at 2500 g for 10 min at 4°C, and was suspended in an equal volume of 2 x SDS sample buffer (2% SDS, 20 mM Tris-HCl [pH 6.8], and 20% sucrose). Fibroblasts were used between passages 3 and 7. In some experiments, fibroblasts were cultured on the plates which were coated with 30 µg/cm² fibronectin, 30 µg/cm² laminin (each from Chemicon International Inc., Temecula, CA, USA), or 30 µg/cm² type I collagen (Koken, Tokyo, Japan).

Gelatin Zymography
Gelatin zymography was performed in 10% SDS-polyacrylamide gels impregnated with 2 mg/mL gelatin which had been labeled fluorescently with 2-methoxy-2,4-diphenyl-3(2H)-furanone as previously described (Kubota et al., 2000,2001). The lysis of gelatin was visualized under long-wave UV light, and gelatinolytic activities and activity ratios (62-kDa MMP-2 activities/72-kDa and 62-kDa MMP-2 activities) were calculated from the integrated density of each band by a computer system. Purified MMP-2 from human fibrosarcoma (Yagai Co., Yamagata, Japan) was used as the control. The integrated density of the band showed a linear relationship with gelatinolytic activity of the enzyme from 0 mU to 150 mU. Finally, the gel was stained with Coomassie Brilliant Blue R250, and then de-stained.

Western Immunoblotting
Samples were run on 10% SDS-polyacrylamide gels, and transferred onto nitrocellulose paper at 100 mA for 18 hrs as previously described (Kubota et al., 2000). After incubation with 5% bovine serum albumin in TBST (150 mM NaCl, 10 mM Tris-HCl [pH 8.0], 0.05% Tween-20, and 0.02% NaN₃) for 1 hr, the nitrocellulose papers were incubated with a 1:100 dilution of monoclonal antibody against MMP-2 (Calbiochem, Cambridge, MA, USA), or a 1:500 dilution of polyclonal antibody against MT1-MMP, MT2-MMP, or MT3-MMP (each from Calbiochem, La Jolla, CA, USA), and were developed by a horseradish peroxidase ABC kit.

RNA Extraction and Non-radioisotopic Quantitative Reverse-transcriptase/Polymerase Chain-reaction (RT-PCR)
Total cellular RNA was extracted from fibroblasts by means of Trizol reagent according to the manufacturer's protocol (Gibco/BRL, Gaithersburg, MD, USA). First-strand cDNA was synthesized from 3 µg total RNA. Briefly, RNA was incubated in 20 U RNasin ribonuclease inhibitor (Promega, Madison, WI, USA), 0.5 mM dNTP (0.5 mM each dATP, dCTP, dGTP, dTTP) (Pharmacia Chemicals, Uppsala, Sweden), 0.5 µg oligo-(dT)^12-18 (Pharmacia Chemicals, Uppsala, Sweden), 10 mM dithiothreitol, and 100 U RNase H^- reverse transcriptase (BRL, Gaithersburg, MD, USA) at 37°C for 1 hr.

PCR amplification was performed with the use of 25 µL of cDNA reaction mixture containing 10 mM Tris-HCl (pH 9.0), 50 mM KCl, 0.1% Triton X-100, 2.5 mM MgCl₂, 0.2 mM each of dNTP, 0.4 mM upstream and downstream primers, and 2.5 U Taq DNA polymerase (Perkin-Elmer Cetus, Emeryville, CA, USA) (Ohyama et al., 1996). The specific primers for MT1-MMP (upstream primer, 5^'-AATGACATCTTCCTGGTGGC-3^'; downstream primer, 5^'-GAGCAGCATCAATCTTGTCG-3^'), MT2-MMP (upstream primer, 5^'-CAGCCCAGCCGCCATATGTC-3^'; downstream primer, 5^'-CTTTCACTCGTACCCCGAAC-3^'), MT3-MMP (upstream primer, 5^'-CCGACTAGCCCCAGAATGTC-3^'; downstream primer, 5^'-TTGGAGCTACCTCTTGTCTG-3^'), and β-actin (upstream primer, 5^'-GTGGGGCGCCCCAGGCACCA-3^'; downstream primer, 5^'-CTCCTTAATGTCACGCACGATTTC-3^') were synthesized (Ohyama et al., 1996; Kitagawa et al., 1998). The cDNA amplification was carried out with a DNA thermal cycler (Perkin-Elmer Cetus) with a cycle program of 96°C for 30 sec, 65°C for 30 sec, and 72°C for 45 sec, followed by a final extension step at 72°C for 10 min. PCR products were resolved by electrophoresis on 1.8% agarose gels, and detected by ethidium bromide staining. The images of the gels were captured into a computer system, and then the intensity of each band was calculated. The relative amounts of MT1-MMP, MT2-MMP, and MT3-MMP mRNAs were calculated by normalization with the amount of β-actin mRMA as previously described (Yokoi et al., 1993).

Statistical Analysis
Data are expressed as mean ± SE. The Mann-Whitney U-test was used for statistical analyses, and p values < 0.05 were considered significant.

	RESULTS

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Effects of ECMs and IL-1 on Gelatinases
Fibroblasts isolated from odontogenic keratocysts secreted 72-kDa gelatinase spontaneously, and 1 nM rhIL-1 slightly increased the secretion of 62-kDa gelatinase (Fig. 1). Immunoblotting with the anti-MMP-2 antibody revealed that the 72-kDa and 62-kDa gelatinases were proMMP-2 and the active form of MMP-2, respectively (data not shown). When the fibroblasts were cultured on fibronectin-, laminin-, and type I collagen-coated dishes, type I collagen enhanced the activation of proMMP-2, while neither fibronectin nor laminin affected the activation of proMMP-2. In addition, rhIL-1 further enhanced the type I collagen-induced activation of proMMP-2 in a concentration-dependent manner (Fig. 2). The activity ratio was increased from 0.17 ± 0.11 (n = 4) to 0.63 ± 0.25 (n = 4) by 10 nM rhIL-1. The half-maximum response was obtained at 0.04 nM rhIL-1. The rhIL-1-induced activation of proMMP-2 was inhibited by the anti-hIL-1 antibody (Fig. 1). When the fibroblasts were cultured on type I collagen-coated dishes without rhIL-1 for 48 hrs, and then the collected conditioned medium was incubated with the fibroblasts grown on type I collagen-coated dishes in the absence of rhIL-1 for 18 hrs, no additional activation of the spontaneously secreted proMMP-2 was detected. However, when the collected condition medium was incubated with the fibroblasts grown on type I collagen-coated dishes in the presence of rhIL-1, the additional activation of proMMP-2 was induced. On the other hand, when the collected condition medium was incubated on type I collagen-coated dishes with rhIL-1 in a cell-free condition, the activation of proMMP-2 was limited (Fig. 3).

View larger version (30K): [in this window] [in a new window]   Figure 1. Effects of ECMs on gelatinases secretion in odontogenic keratocyst fibroblasts. Gelatin zymography of culture media. Fibroblasts were cultured on plastic plates (lanes 1 and 2), or 30 µg/cm2 fibronectin (lanes 3 and 4)-, 30 µg/cm2 laminin (lanes 5 and 6)-, or 30 µg/cm2 type I collagen (lanes 7, 8, and 9)-coated dishes in serum-free DMEM for 48 hrs at 37°C in the presence (lanes 2, 4, 6, 8, and 9) or absence (lanes 1, 3, 5, and 7) of 1 nM rhIL-1. Anti-hIL-1 antibody (Anti-IL-1) was added to the culture media prior to incubation with rhIL-1 (lane 9). The culture media (30 µL) were subjected to gelatin zymography. Similar results were seen in four independent experiments.

View larger version (19K): [in this window] [in a new window]   Figure 2. Effects of IL-1 on the activation of proMMP-2 in odontogenic keratocyst fibroblasts cultured on type I collagen-coated dish. Fibroblasts were cultured in serum-free DMEM in the absence (0) or presence of various concentrations of rhIL-1 (0.01-10 nM) on plastic plates () or 30 µg/cm2 type I collagen-coated dishes () for 48 hrs at 37°C. Activity ratio of MMP-2 was calculated as described under "MATERIALS & METHODS". Vertical bars indicate mean ± SE (n = 4). *p < 0.05 compared with the value of the cells grown on type I collagen-coated dishes without rhIL-1.

View larger version (49K): [in this window] [in a new window]   Figure 3. Effects of fibroblasts on proMMP-2 activation. Fibroblasts were cultured on 30 µg/cm2 type I collagen-coated dishes in serum-free DMEM for 48 hrs at 37°C. Then, the collected culture media were incubated with (lanes 1 and 2) or without (lane 3) the fibroblasts cultured on type I collagen-coated dishes for 18 hrs at 37°C in the absence (lane 1) or presence (lanes 2 and 3) of 1 nM rhIL-1. The culture media (30 µL) were subjected to gelatin zymography. Similar results were seen in four independent experiments.

Effects of IL-1 and Type I Collagen on MT-MMPs Expression

View larger version (26K): [in this window] [in a new window]   Figure 4. Effects of IL-1 and type I collagen on the expression of MT1-MMP mRNA and protein in odontogenic keratocyst fibroblasts. Agarose gel of the PCR products of MT1-MMP and β-actin (A) and Western immunoblotting for MT1-MMP (B). Odontogenic keratocyst fibroblasts were incubated on plastic plates (lanes 1 and 2) or 30 µg/cm2 type I collagen-coated dishes (lanes 3 and 4) in the absence (lanes 1 and 3) or presence (lanes 2 and 4) of 1 nM rhIL-1 for 48 hrs at 37°C. (A) Total cellular RNA was extracted, and PCR amplification was performed at 35 cycles. The PCR products of MT1-MMP and β-actin were resolved by electrophoresis on 1.8% agarose gel. (B) The fibroblasts were lysed in SDS sample buffer, and the aliquots of cell lysates were subjected to Western immunoblotting for MT1-MMP as described under "MATERIALS & METHODS". Similar results were seen in six independent experiments.

	DISCUSSION

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The fibroblasts isolated from odontogenic keratocysts secreted proMMP-2 spontaneously. The secreted proMMP-2 was slightly activated when the cells were cultured on type I collagen, as previously shown in other types of cells, such as normal fibroblasts and carcinoma cell line (Seltzer et al., 1994; Gilles et al., 1997). The most interesting finding in this study is that rhIL-1 further enhanced the type I collagen-dependent activation of proMMP-2 in the fibroblasts. Type I collagen is widely expressed not only in bone but also in the fibroblasts of the subepithelial layers of odontogenic keratocysts (unpublished observation). IL-1 is also expressed in the epithelial cells and the subepithelial fibroblasts of odontogenic keratocysts (Meghji et al., 1992,1996; Kubota et al., 2001). IL-1 is not degraded by MMP-1, -2, -3, or -9 (Ito et al., 1996). Therefore, the activation of proMMP-2 in the fibroblasts of odontogenic keratocysts may be dependent on the intensities of IL-1 expression.

In vitro experiments have shown that proMMP-2 is resistant to serine proteinases such as plasmin, plasma kallikrein, neutrophil elastase, and trypsin (Okada et al., 1990). We also found that the rhIL-1-induced activation of proMMP-2 in the fibroblasts cultured on type I collagen-coated dishes was not inhibited by protease inhibitors such as -amino caproic acid, pepstatin A, and leupeptin (data not shown). Therefore, this activation of proMMP-2 is not induced by serine, cystein, or aspartate proteases. Furthermore, the additional activation of proMMP-2 by IL-1 was not detected in the fibroblast-free condition, suggesting that a plasma-membrane-associated factor which is induced on the fibroblasts by IL-1 and type I collagen may be important for the activation of proMMP-2.

MT1-, MT2-, and MT3-MMPs can activate proMMP-2 (Sato et al., 1994; Takino et al., 1995; Will and Hinzmann., 1995; Imai et al., 1997). We have shown in this study that the expression of MT1-MMP mRNA and protein was increased in the fibroblasts isolated from odontogenic keratocysts by rhIL-1 when the cells were cultured on type I collagen. It has been shown that MT1-MMP is synthesized as a 63-kDa protein, and the 60-kDa active form binds MMP-2 at the cell surface (Lehti et al., 1998). The detected MT1-MMP on the fibroblasts in this study was the 60-kDa active form, although the fibroblasts expressed 63-kDa MT1-MMP when the cells were incubated with ionomycin (data not shown), as previously reported (Lehti et al., 1998). It has been shown that the tissue inhibitor of metalloproteinase-2 (TIMP-2) binds both proMMP-2 and MT1-MMP, and the MT1-MMP-TIMP-2 complex regulates the proMMP-2 activation (Strongin et al., 1995). On the other hand, many studies have shown that proMMP-2 is activated proportionally with the increase in the expression of MT1-MMP in various types of cells (Imai et al., 1997; Nakamura et al., 1999). Further studies including TIMP-2 expression are needed to clarify the regulatory mechanisms of proMMP-2 activation in the fibroblasts.

In addition to the role of MT1-MMP as a membrane-bound activator of proMMP-2, it has been shown that MT1-MMP can degrade several extracellular matrix proteins such as gelatin, fibronectin, vitronectin, and types I, II, and III collagen (d'Ortho et al., 1997; Ohuchi et al., 1997). This suggests that the high expression of MT1-MMP may participate in cyst expansion through the direct enzymatic degradation of the bone.

In summary, the results from this study have demonstrated, first, that IL-1 increases MT1-MMP expression synergistically with type I collagen in the fibroblasts isolated from odontogenic keratocysts, and then induces activation of proMMP-2 secreted from the fibroblasts. These findings support the hypothesis that IL-1 stimulates enzymatic degradation of the extracellular matrices of the bone around the cysts, and induces odontogenic keratocyst expansion.

	ACKNOWLEDGMENTS

 
This work was supported by a Grant-in-Aid from the Ministry of Education of Japan (No. 09672054).

Received for publication March 19, 2001. Revision received November 5, 2001. Accepted for publication November 28, 2001.

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Journal of Dental Research, Vol. 81, No. 1, 23-27 (2002)
DOI: 10.1177/154405910208100106


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