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PubMed1996

Characterization of a glomerular epithelial cell metalloproteinase as matrix metalloproteinase-9 with enhanced expression in a model of membranous nephropathy.

The role of the glomerular visceral epithelial cell in the physiologic turnover and pathologic breakdown of the glomerular extracellular matrix has remained largely unexplored. In this study a 98-kD neutral proteinase secreted by cultured rat visceral glomerular epithelial cells was shown to be a calcium, zinc-dependent enzyme secreted in latent form. In addition, the protein was heavily glycosylated and demonstrated proteolytic activity against Type I gelatin, Type IV collagen gelatin, and fibronectin. The similarity in molecular mass and substrate specificities to the 92-kD human matrix metalloproteinase-9 (MMP-9, or gelatinase B) suggested the identity of this activity, which was confirmed by immunoprecipitation and Northern blot analysis. The differences in molecular mass (98 vs. 92 kD) were not due to species-specific differences in glycosylation patterns, since cultured rat peritoneal macrophages secreted MMP-9 as a 92-kD enzyme. Furthermore, transfection of the human MMP-9 cDNA into rat glomerular epithelial cells yielded the 98-kD product. Using a specific monoclonal anti-MMP-9 antibody and in situ reverse transcription (ISRT) analysis of MMP-9 mRNA, the expression of this enzyme was evaluated in vivo. Normal rat glomeruli expressed little immunohistochemical or ISRT staining for MMP-9, while in rats with passive Heymann nephritis there was a major increase in MMP-9 protein and mRNA staining within the visceral epithelial cells. The temporal patterns of MMP-9 expression correlated with the period of proteinuria associated with this model, suggesting that a causal relationship may exist between GEC MMP-9 expression and changes in glomerular capillary permeability.

Animals↗
PubMed2000

Tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 9, and neopterin in the cerebrospinal fluid: preferential presence in HTLV type I-infected neurologic patients versus healthy virus carriers.

The human retrovirus HTLV-I is responsible for the chronic progressive myelopathy, TSP/HAM, characterized by the presence of infiltrated T lymphocytes, cytokines, and matrix metalloproteinases (MMPs) within spinal cord lesions. MMPs have been associated with several neurological diseases, and we previously reported the specific presence of the extracellular matrix-degrading protease, MMP-9, in the cerebrospinal fluid of TSP/HAM patients. Nevertheless, previous studies have not yet shown whether the expression of MMP-9 is associated with HTLV-I infection per se, or with neurological symptoms following infection. In the present work, the presence of tissue inhibitors of metalloproteinases 1 and 3 (TIMP-1 and TIMP-3) and of MMP-9 in the CSF of HTLV-I-infected individuals was compared in TSP/HAM patients versus HTLV-I carriers without neurological symptoms. TIMP-3, a regulator of MMP activity and cell survival, was detected with a significantly higher frequency in the TSP/HAM group and paralleled the increased levels of MMP-9 and neopterin, a sensitive indicator of cellular immune activation. These data may reflect the intense cell remodeling that occurs intrathecally in inflamed tissue. Changes in MMP, TIMP, and neopterin expression were not related to age at onset of disease, grade of motor disability, progressor status, or duration of disease, presumably indicating that TSP/HAM patients are continuously subjected to viral and immunological pressure. All these observations suggest that TIMPs and MMPs may contribute to the pathogenesis of TSP/HAM, and hence a new therapeutic strategy targeting the MMP/TIMP balance is needed. These observations also suggest that MMP-9 and TIMP-3 in CSF may be useful markers in the follow-up of the efficacy of therapeutic trials in TSP/HAM patients.

Biomarkers↗
PubMed2000

Matrix metalloproteinases in human gliomas: activation of matrix metalloproteinase-2 (MMP-2) may be correlated with membrane-type-1 matrix metalloproteinase (MT1-MMP) expression.

To evaluate possible roles of matrix metalloproteinase (MMP)-1, -2, tissue inhibitor of metalloproteinase (TIMP)-1, -2 and membrane-type-1 matrix metalloproteinase (MT1-MMP) in invasion of human gliomas, expressions of these proteins were investigated in ten cases of human glioma and two meningioma tissues and eight human glioma cell lines. In gelatin zymography, MMP-2 activities of glioblastomas were higher than astrocytomas. The activated form of MMP-2 was seen in five of six cases of glioblastomas, but not in astrocytomas. MMP-9 activity was detected in all cases of malignant astrocytomas but the reactivity of MMP-9 was weaker than that of MMP-2. MT1-MMP mRNA expression in glioblastomas was higher than that in astrocytomas. Five cases of glioblastomas with activated form of MMP-2 had MT1-MMP expressions. In vitro, human glioma cell lines with high expression of MT1-MMP also showed high MMP-2 activity. TIMP-1 transcripts were constitutively present in almost all glioma tissues and cell lines, whereas TIMP-2 mRNA were weak especially in malignant gliomas. Imbalance of TIMP-2/MMP-2 was observed using immunoprecipitation analysis in a glioma cell line. High expression of MMP-2 and MT1-MMP is possibly involved in invasiveness of malignant glioma.

Animals↗
PubMed2003

Differences in estrogen modulation of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-1 expression in cultured fibroblasts from continent and incontinent women.

OBJECTIVE: The purpose of this study was to investigate the effect of increasing estrogen concentrations on metalloproteinase and tissue inhibitors of metalloproteinase protein expressions in cultured pelvic fibroblasts that were obtained from continent and incontinent women. STUDY DESIGN: Periurethral vaginal wall tissues were taken from four stress incontinent and three continent premenopausal women who underwent gynecologic surgery for benign indications. Protein was extracted from these tissues, and Western blot analysis was performed to document that fibroblasts from continent and incontinent women differed with respect to metalloproteinase and tissue inhibitors of metalloproteinase production. One age-matched tissue pair was prepared for fibroblast culture. Cells were cultured with increasing concentrations of estradiol (0-500 pg/mL). Extracellular metalloproteinase and tissue inhibitors of metalloproteinase were assessed semiquantitatively with Western blotting. RESULTS: Periurethral vaginal tissues from incontinent women expressed less tissue inhibitors of metalloproteinase when compared with tissue from the control subjects; there was no difference in the expression of cleaved, active metalloproteinase protein. Tissue inhibitors of metalloproteinase expression from fibroblasts of continent women significantly increased with increasing estradiol concentrations (0-100 pg/mL, P <.05). No significant dose response was seen in fibroblasts from an incontinent woman. Metalloproteinase expression was not altered by increasing estradiol concentrations in fibroblasts from either continent or incontinent women. CONCLUSION: This preliminary in vitro study suggested that, in fibroblasts that were derived from the continent woman, tissue inhibitors of metalloproteinase protein production increases with increasing estrogen levels and that, in stress incontinent fibroblasts, no similar increase occurs. Neither group demonstrated a change in metalloproteinase production in response to varying estrogen levels, which suggests that estrogen may inhibit collagen degradation in continent women by increasing tissue inhibitors of metalloproteinase production but exerts a reduced inhibitory effect on collagenolysis in women with stress urinary incontinence.

Adult↗
PubMed1997

Human thyroid carcinoma cell lines and normal thyrocytes: expression and regulation of matrix metalloproteinase-1 and tissue matrix metalloproteinase inhibitor-1 messenger-RNA and protein.

Matrix metalloproteinase-1 (MMP-1) and tissue matrix metalloproteinase inhibitor 1 (TIMP-1) play an important role in remodeling the extracellular matrix in normal and pathological processes. The effect of phorbol-myristate acetate (PMA), interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-alpha) on MMP-1 and TIMP-1 expression was studied on highly purified thyrocytes and undifferentiated 8505 C, C 643, HTh 74, SW 1736 thyroid carcinoma cells compared with thyroid-derived fibroblasts. Messenger RNA (mRNA) levels were monitored by competitive semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) after 24 hours. Culture supernatants were assayed for free and/or complexed MMP-1 and TIMP-1 after 48 hours using enzyme-linked immunosorbent assay (ELISA) systems (detection limit: <2 ng/mL). MMP-1 and TIMP-1 mRNA were present in all cell types, although thyrocytes showed MMP-1 mRNA levels near the detection limit. 8505 C expressed MMP-1 mRNA levels of up to 10(6) times those of the other cells analyzed. PMA and IL-1 increased MMP-1 mRNA in most cell types. TIMP-1 mRNA increased after treatment with PMA in all cells except 8505 C, whereas only slight effects were shown after IL-1 stimulation. MMP-1 protein was undetectable in normal thyrocyte cultures, but was secreted spontaneously by all cell lines ([ng/mL]; C 643: 15+/-7; HTh 74: 81+/-1; SW 1736: 13+/-2; 8505 C: 2097+/-320). There was a strong correlation between levels of MMP-1 mRNA and protein (r = 0.99, p < .0001). PMA and IL-1 increased MMP-1 secretion in all cell types after 48 hours. Fibroblasts ([ng/mL] 517+/-55) and the cell lines (C 643: 142+/-48; HTh 74: 115+/-13; SW 1736: 202+/-14; 8505C: 120+/-19) secreted TIMP-1 in unstimulated cultures, whereas only a trace amount was detected in thyrocyte cultures, even after PMA treatment. IL-1 upregulated TIMP-1 secretion after 48 hours in SW 1736, HTh 74, and C 643 cells. Our data suggest that in contrast to normal thyrocytes, dedifferentiated thyroid carcinoma cell lines are potential producers of MMP-1 as well as TIMP-1. High MMP-1 or MMP-1/TIMP-1 expression may play a role in tissue invasion of undifferentiated thyroid cancer cells.

Adult↗
PubMed2001

Systematic separation and purification of elastase, gelatinase (matrix metalloproteinase 9), and collagenase (matrix metalloproteinase 8) from polymorphonuclear leukocytes in dialyzers previously used by patients with renal failure.

We developed a simple and effective method for the systematic separation and purification of human polymorphonuclear leukocyte (PMN) proteinases, elastase, gelatinase (matrix metalloproteinase 9, type IV collagenase), and collagenase (matrix metalloproteinase 8), derived from the extracts of hollow fiber dialyzers that had been utilized in the treatment of patients with renal failure. The fraction containing elastase was grossly separated from that containing gelatinase and collagenase by heparin-Sepharose chromatography and purified in an aprotinin column. The remaining two enzymes were then separated using the gelatin-Sepharose column after gel chromatography following ammonium sulfate precipitation. Gelatinase and collagenase were further purified by gelatin-Sepharose chromatography as a latent form and by collagen-Sepharose chromatography as an activated form. This novel method offers procedural advantages over existing methods that separate PMNs from the whole blood of volunteers for experimental research purposes.

Animals↗
PubMed2001

Spectrum of matrix metalloproteinase expression in primary and metastatic colon cancer: relationship to the tissue inhibitors of metalloproteinases and membrane type-1-matrix metalloproteinase.

The matrix metalloproteinases, MMP-2 and MMP-9, are capable of degrading components of the basement membrane, a vital barrier breached during the progression of colorectal cancer. The regulation of MMP-2 activation and subsequent targets is vital to understanding the metastatic process. MMP-2 was not expressed by colorectal cancer cells (C170 and C170HM(2)) in vitro but by stromal fibroblasts (46BR.1GI). There was induction of this MMP upon transwell co-cultivation of the colon cancer cells with the fibroblasts but in vivo growth did not lead to a similar increase in the metastatic tumour cells (C170HM(2)), MMP-2 again being attributed to the stromal cells. MMP-2 mRNA was overexpressed in human colorectal tumours compared to normal colorectal tissue, which correlated with Dukes' stage and immunolocalized to the stromal compartment of the tumour tissue. The active form of the MMP-2 enzyme was also present in the colorectal tumour tissue (7/8) but essentially absent in all normal colon samples examined (1/8). MMP-2 activation was not related to an increase in MT-1-MMP mRNA or a decrease in the specific inhibitor TIMP-2 in human tissue. There was however an increase in MMP-2/TIMP-2 ratio in tumour compared to normal. MMP-9, a target of active MMP-2, was present in the metastatic cell line but expression was down-regulated in the tumour cells in vivo, gelatin analysis revealed that MMP-9 was almost entirely attributable to the murine host, confirmed by PCR. There was no increase in mRNA for MMP-9 or its specific inhibitor TIMP-1 in colorectal tumour tissue compared to normal, MMP-9 protein localized to the inflammatory infiltrate. Fibroblast cells may provide malignant epithelial cells with a ready source of enzyme which is crucial to the metastatic process.

Colonic Neoplasms↗
PubMed2003

[Expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in the hepatocellular carcinomas].

OBJECTIVE: To explore the expression and clinical prognostic significance of matrix metalloproteinase-2 mRNA (MMP-2 mRNA), tissue inhibitor of matrix metalloproteinase-2 mRNA (TIMP-2 mRNA), matrix metalloproteinase-2 protein (MMP-2), matrix metalloproteinase-9 protein (MMP-9), tissue inhibitor of matrix metalloproteinase-1 protein (TIMP-1), and tissue inhibitor of matrix metalloproteinase-2 protein (TIMP-2) in the hepatocellular carcinomas (HCCs). METHODS: Fifty-six specimens of HCCs from 56 patients, who were followed-up, were investigated by in situ hybridization with specific probes for MMP-2, TIMP-2, and by immunohistochemistry with anti-MMP-2, MMP-9 and anti-TIMP-1, TIMP-2 monoclonal antibody. We analyzed the data with chi-square test, spearmans correlation analysis, monovariate Kaplan-Meier plot and multivariate Cox regression analysis. RESULTS: 1. The positive expression of MMP-2mRNA, TIMP-2mRNA, MMP-2 protein, MMP-9 protein, TIMP-1 protein and TIMP-2 protein in the 56 HCCs cases were 48 (85.7%), 35 (62.5%), 44 (78.6%), 41 (73.2%), 30 (53.6%), and 38 (68%), respectively. 2. We found over-expression of MMP-2 mRNA, MMP-2 protein, and MMP-9 protein, but low expression of TIMP-1 protein in the 56 cases of HCCs (P < 0.01, P < 0.05). 3. There was a positive association between TIMP-2mRNA and TIMP-2 protein expression, and between MMP-2 mRNA and MMP-2 protein in HCCs, respectively (r = 0.316, P < 0.05; r = 0.356, P < 0.05). 4. Over-expression of MMP-2 mRNA was positively correlated to the tumor size and TNM classification (r = 0.441, P < 0.001; r = 0.340, P < 0.05), and MMP-9 protein was related to shortened survival (P < 0.05). 5. In both monovariate Kaplan-Meir plot and multivariate Cox regression analysis, the expression of MMP-2 protein and MMP-9 protein were linked to unfavorable prognosis. These results were further confirmed by multivariate analysis in which MMP-2 protein and MMP-9 protein emerged as independent prognostic factors for poor survival regardless of the age, tumor size, tumor grades, TNM classification and expression of MMP-2mRNA, TIMP-2mRNA, TIMP-1 protein and TIMP-2 protein. The hazard ratios of expression of MMP-2 protein and MMP-9 protein were 3.875 and 4.528, respectively. CONCLUSION: The over-expression of MMP-2mRNA, MMP-2 protein and MMP-9 protein and the imbalance between MMP-2 and TIMP-2 play pivotal roles in the degradation of excellular matrix of HCCs. MMP-2 and MMP-9 immunoreactive protein have been closely related to a shortened survival independent of major prognostic indicators in the primary HCC and increase the risk of the patients after the operation.

Adult↗
PubMed2005

[Comparison of doxycycline, losartan, and their combination on the expression of matrix metalloproteinase, tissue inhibitor of matrix metalloproteinase, and collagen remodeling in the noninfarcted myocardium after acute myocardial infarction in rats].

OBJECTIVE: To compare the effects of matrix metalloproteinase (MMP) inhibitor doxycycline, losartan, and their combination on the expression of MMP-8, 13, tissue inhibitor of MMP-1, 2 (TIMP-1, 2), and collagen remodeling in the noninfarcted myocardium after acute myocardial infarction (AMI) in rats. METHODS: Two hundred and fifty-four AMI rats, induced by left coronary ligation, were randomly assigned to the following groups: (1) AMI controls group (n = 64); (2) doxycycline group (30 mg x kg(-1) x d(-1), n = 63); (3) losartan group (10 mg x kg(-1) x d(-1), n = 62); (4) concomitant doxycycline and losartan group (30 and 10 mg x kg(-1) x d(-1) respectively, n = 65); and (5) Sham-operated rats (n = 30), which were randomly selected to serve as noninfarction controls. Each group was further divided into three subgroups of 1, 2, and 4 weeks that received treatment. After the completion of treatment, the rats were killed. The mRNA and protein expression of MMPs and TIMPs in the noninfarcted myocardium were quantified by RT-PCR and Western blot, respectively. The type I and type III collagen volume fraction (CVF) of the noninfarced myocardium were assessed immunohistochemically. RESULTS: No significant difference existed in myocardial infarction sizes among the 12 subgroups of AMI controls and the three treatment groups (42%-48%, all P > 0.05). Compared with sham operated rats, the mRNA and protein expression of MMP-8 and 13 significantly increased by 39%-183% in all three subgroups of AMI controls (all P < 0.05), except both of their mRNA expressions in 2-week subgroups; the mRNA and protein levels of TIMP-1 increased only in 1-week subgroup of AMI controls by 104% and 67%, respectively (both P < 0.05); the mRNA of TIMP-2 increased in all 1, 2, and 4-week subgroups by 144%-232% (all P < 0.05), but its protein expression lagged and only enhanced in 2 and 4-week subgroups of AMI controls by 231% and 332%, respectively (both P < 0.05). Meanwhile, both type I and type III CVF of noninfarcted myocardium significantly increased in all three subgroups of AMI controls (type I CVF: 3.01%-5.64% vs 1.53%-1.67%, P < 0.01-0.001; type III CVF: 2.19%-4.42% vs 1.46%-1.59%, P < 0.05-0.001), with type I CVF being higher in 4-week than in 1 and 2-week subgroups (5.64% vs 3.01% and 3.02% respectively, all P < 0.05). Compared with AMI controls, all three kinds of treatment significantly reduced the increased mRNA and protein expressions of MMP-8, 13 and TIMP-1, 2 after AMI by 14%-60% (all P < 0.05), as well as type I/III CVF in their 2 and 4-week subgroups (type I CVF: 1.56%-2.38% vs 3.02%-5.64%, P < 0.05-0.001; type III CVF: 1.92%-2.65% vs 4.19%-4.42%, P < 0.05-0.01), except for doxycycline's effect on type III CVF in any of its three subgroups (all P > 0.05). Among the three treatment groups, significant differences existed in the above mentioned indicators only at some subgroup levels (all P < 0.05). CONCLUSIONS: Like losartan, doxycycline can also suppress the enhanced mRNA and protein expression of MMP-8, 13 and TIMP-1, 2, and reduce type I collagen deposition in the noninfarcted myocardium after AMI in rats. However, it has no effect on type III collagen deposition.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms.

BACKGROUND AND PURPOSE: We studied matrix metalloproteinases (MMP) 2, 8, and 9 and extracellular matrix metalloproteinase inducer (EMMPRIN) levels in relation to carotid atherosclerotic plaque characteristics. METHODS: Carotid atherosclerotic plaques (n=150) were stained and analyzed for the presence of collagen, smooth muscle cell (SMC), and macrophages. Adjacent segments were used to isolate total protein to assess MMP-2 and MMP-9 activities and gelatin breakdown, MMP-8 activity, and EMMPRIN levels. RESULTS: Macrophage-rich lesions revealed higher MMP-8 and MMP-9 activities, whereas SMC-rich lesions showed higher MMP-2 activity. The levels of less glycosylated EMMPRIN-45kD were higher in SMC-rich lesions and lower in macrophage-rich plaques. EMMPRIN-45kD was associated with MMP-2 levels, whereas EMMPRIN-58kD was related to MMP-9 levels. CONCLUSIONS: MMP-2, MMP-8, and MMP-9 activities differed among carotid plaque phenotypes. Different EMMPRIN glycosylation forms are associated with either MMP-2 or MMP-9 activity, which suggests that EMMPRIN glycosylation may play a role in MMP regulation and plaque destabilization.

Analysis of Variance↗
PubMedDate not supplied

Differential regulation of stromelysin-1 (matrix metalloproteinase-3) and matrilysin (matrix metalloproteinase-7) in baboon endometrium.

OBJECTIVE: To investigate in vivo expression of matrix metalloproteinase enzymes (MMP), MMP-3 and MMP-7, by the baboon endometrium in relation to the process of tissue remodeling that accompanies menstruation in the primate. METHODS: Endometrial tissues and uterine fluids obtained from reproductively intact cycling baboons, cycling baboons treated with an anti-progestin, and ovariectomized steroid-treated baboons were evaluated for MMP mRNA expression and protein production by using multiple analytic techniques. RESULTS: The pattern of MMP protein production matched the pattern of MMP mRNA expression. In intact cycling baboons, MMP mRNA expression and protein production were specific to cell type and stage of the menstrual cycle. Endometrial stroma expressed minimal amounts of MMP-3 during the proliferative and secretory stages, whereas endometrial epithelia expressed MMP-7 during the proliferative stage. Expression of stromal MMP-3 and epithelial MMP-7 increased during early menses. Administration of anti-progestin beginning on the day of the LH surge increased MMP-7 but not MMP-3 expression at the mid secretory phase. Expression of MMP-3 and MMP-7 in the ovariectomized steroid-treated animals paralleled that of the intact cycling animals. CONCLUSIONS: These results highlight the similarity of human and baboon endometrial MMP-3 and MMP-7 production, providing further evidence for use of the baboon as a model for studying events associated with hormonally regulated changes during the menstrual cycle. These results also demonstrate that endometrial epithelial MMP-7 is suppressed by progesterone in the baboon endometrium, but endometrial stromal MMP-3 is regulated by a different mechanism.

Amino Acid Sequence↗
PubMed1998

Inhibition of interleukin-1alpha-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid.

OBJECTIVE: To determine whether matrix metalloproteinases (MMPs) degrade cartilage oligomeric matrix protein (COMP) to produce fragments similar to those found in synovial fluid (SF) from patients with arthritis. METHODS: COMP fragments were generated in vitro by treating (a) bovine articular cartilage with interleukin-1alpha (IL-1alpha), (b) purified bovine COMP with MMPs, and (c) articular cartilage with MMPs. The fragments generated in each case were analyzed by Western blot, using an antibody to the C-terminal heptadecapeptide of COMP. RESULTS: IL-1alpha stimulation of cartilage resulted in a fragmentation of COMP, which was inhibited by MMP inhibitors CGS 27023A and BB-94. Isolated, recombinant MMPs rapidly degraded purified COMP, as well as COMP residing in cartilage. Several COMP fragments produced in vitro had similar electrophoretic mobility to those in SF of patients with arthritis. CONCLUSION: MMPs may contribute to the COMP fragments found in vivo. Quantitation of MMP-specific fragments may be useful in the evaluation of MMP inhibitors in patients with arthritis.

Animals↗
PubMed2005

Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque.

From experimental and clinical studies it is known that matrix conservation and degradation by matrix metalloproteinases (MMPs) plays a major role in plaque progression and destabilization with related onset of acute vascular events such as acute coronary syndromes or cerebrovascular accidents. Recently, extracellular MMPs inducer (EMMPRIN) has been reported to induce and activate the expression of MMPs in myocardium and plays an important role in the ventricular remodeling in human heart failure. Similarly to heart failure myocardium, EMMPRIN may be expressed in human atheroma and play a role in the extracellular matrix (ECM) remodeling and atherogenic cell differentiation. This study was designed to investigate the possible biological role of EMMPRIN in human atheroma. Immunohistochemical analysis for MMPs and EMMPRIN was performed on human carotid endarterectomy specimens and control aortas. EMMPRIN showed significant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage/monocyte infiltrates in atherosclerotic intima, plaque itself and vascular smooth muscle cells (VSMCs). Zymography and Western blot analysis revealed EMMPRIN expression in the carotid atheromas, but not in the control aortas. Human bone marrow monocytes, which were cultured with atherogenic proinflammatory cytokine stimulation revealed increased EMMPRIN and MMPs expressions. ECM remodeling is under the control of induction and inhibition of matrix degrading protease and the novel MMP inducer, EMMPRIN may play a role in influx and differentiation of monocytes and destabilizing atheroma.

Adolescent↗
PubMed2007

Matrix metalloproteinases, tissue inhibitor of matrix metalloproteinase-1, and laminin-5 gamma2 chain immunolocalization in gingival tissue of endotoxin-induced periodontitis in rats: effects of low-dose doxycycline and alendronate.

BACKGROUND: Matrix metalloproteinases (MMPs) play important roles in tissue destruction mechanisms of periodontitis. MMP-8 and -13 are the major collagenases that act in extracellular matrix degradation in periodontal tissues. MMP-14 is a membrane-type MMP, and laminin (Ln)-5 is a basal membrane component. The aim of the present study was to evaluate the effects of doxycycline and alendronate on gingival tissue expression of MMP-8, -13, and -14; tissue inhibitors of MMP (TIMP)-1; and Ln-5 gamma2 chain in experimental periodontitis induced by Escherichia coli endotoxin (LPS) in rats. METHODS: Experimental periodontitis was induced by repeated injection of LPS. Forty-four adult male Sprague-Dawley rats were divided into five study groups: saline control, LPS, LPS + doxycycline, LPS + alendronate, and LPS + doxycycline + alendronate. Doxycycline and alendronate were given as a single agent or as combination therapy during the 7 days of the experimental study period. On day 7, the rats were sacrificed, and the gingival tissues were analyzed immunohistochemically for expression of MMP-8, -13, and -14, Ln-5 gamma2 chain, and TIMP-1. Alveolar bone loss was evaluated morphometrically under a stereomicroscope. Data were tested statistically by Kruskal-Wallis and Mann-Whitney tests and Spearman correlation analysis. RESULTS: Alveolar bone loss was significantly higher in the LPS, doxycycline, alendronate, and combination groups than in the saline control group (all P <0.01). MMP-8 expression was significantly higher in the LPS group than in the saline control group (P = 0.001). Individual administration of doxycycline or alendronate significantly decreased the expression of MMP-8 compared to LPS (P = 0.01). Combined drug administration reduced MMP-14 significantly compared to doxycycline (P = 0.004). No significant differences in Ln-5 gamma2 chain expression were found between the study groups (P >0.05). MMP-14 significantly correlated with the Ln-5 gamma2 chain in the LPS + alendronate group (P = 0.04) and with the amount of alveolar bone loss in the LPS + doxycycline + alendronate group (P = 0.03). CONCLUSIONS: Our findings suggest that alendronate and/or doxycycline may inhibit MMP-8 expression significantly; particularly, their combined administration may provide beneficial effects in periodontal treatment. Moreover, individual administration of alendronate and doxycycline results in significant increases in TIMP-1 expression in gingiva. However, these effects of combined low-dose doxycycline and alendronate on MMPs and TIMP should be verified by clinical human trials before these agents are used in dental practice.

Alendronate↗
PubMed1997

Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells.

Many of the tumor-associated matrix metalloproteinases that are implicated in metastasis are produced by stromal fibroblasts within or surrounding the tumor in response to stimulation by factors produced by tumor cells. In this study we transfected Chinese hamster ovary cells with putative cDNA for human extracellular matrix metalloproteinase inducer (EMMPRIN), a transmembrane glycoprotein that is attached to the surface of many types of malignant human tumor cells and that has previously been implicated in stimulation of matrix metalloproteinase production in fibroblasts. We show that these transfected cells synthesize EMMPRIN that is extensively post-translationally processed; this recombinant EMMPRIN stimulates human fibroblast production of interstitial collagenase, stromelysin-1, and gelatinase A (72-kDa type IV collagenase). We propose that EMMPRIN regulates matrix metalloproteinase production during tumor invasion and other processes involving tissue remodeling.

Animals↗
PubMed2004

Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase mRNA levels are specifically altered in torn rotator cuff tendons.

BACKGROUND: Rotator cuff tears are a cause of pain and disability in the shoulder. The molecular changes associated with rotator cuff tearing are unclear. A subset of matrix metalloproteinases and tissue inhibitors of metalloproteinase, which are involved in extracellular matrix remodeling and degradation, were evaluated. HYPOTHESIS: There would be an increase in the mRNA level of specific matrix metalloproteinase and a decrease in the mRNA level of specific tissue inhibitors of metalloproteinase in rotator cuff tendon tissue obtained from patients with rotator cuff tears. STUDY DESIGN: Controlled laboratory study. METHODS: Tissue was obtained from 10 patients undergoing rotator cuff repair for full-thickness rotator cuff tears. Also, tissue was obtained from cadaveric specimens with no gross evidence of rotator cuff tearing. Reverse transcription polymerase chain reaction was performed for the collagenases (MMP-1, MMP-8, MMP-13), the stromelysins (MMP-3, MMP-10, MMP-11), and the tissue inhibitors of metalloproteinase (TIMP-1, TIMP-2, TIMP-3, TIMP-4). Western blotting was performed to confirm the mRNA changes demonstrated in collagenase-3 (MMP-13). RESULTS: There was a significant increase in collagenase-3 (MMP-13) mRNA levels, a decrease in stromelysin-1 (MMP-3) mRNA levels, and a decrease in tissue inhibitor of metalloproteinase-2, -3, and -4 mRNA levels. Western blotting demonstrated an increase in the active form of collagenase-3 (MMP-13) in rotator cuff tendon tears. CONCLUSIONS: The mRNA levels of specific matrix metalloproteinases and tissue inhibitors of metalloproteinase are altered in torn rotator cuff tendons. CLINICAL RELEVANCE: With the known action of the matrix metalloproteinases and tissue inhibitors of metalloproteinase in extra-cellular matrix remodeling, these findings suggest that their roles in remodeling of rotator cuff tears should be further investigated.

Aged↗