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PubMed2001

Expression of tissue inhibitor of matrix metalloproteinase-2 correlates with activation of matrix metalloproteinase-2 and predicts poor prognosis in tongue squamous cell carcinoma.

Matrix metalloproteinase 2 (MMP-2) plays a crucial role in invasion and metastasis of malignant tumors. Membrane type 1-MMP (MT1-MMP) was originally identified as an activator of MMP-2. Tissue inhibitor of MMP-2 (TIMP-2) was identified as an inhibitor of MMP-2 and MT1-MMP. However, TIMP-2 was reported to be essential for cell-mediated activation of MMP-2 and thus, the contribution of TIMP-2 to tumor invasion has remained controversial. This study was designed to analyze the role of TIMP-2 for activation of MMP-2 and its prognostic value in tongue squamous cell carcinoma (SCC). Expression of MMP-2, MT1-MMP and TIMP-2 protein was analyzed by immunohistochemistry, and their association with clinical factors was evaluated in 51 patients treated surgically for tongue SCC. Expression of MMP-2, MT1-MMP and TIMP-2 was significantly correlated with local and distant metastatic tumor recurrence and poor prognosis (MMP-2 and MT1-MMP, p < 0.0001; TIMP-2, p = 0.0002). Activation of MMP-2, analyzed by gelatin zymography in 17 fresh specimens, was remarkably associated with expression of MMP-2 (r = 0.779, p < 0.0001), MT1-MMP (r = 0.674, p < 0.0022) and TIMP-2 (r = 0.858, p < 0.0001). Increased expression of TIMP-2, as well as MMP-2 and MT1-MMP, was an important prognostic factor in patients with tongue SCC.

Adult↗
PubMed2001

Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis.

OBJECTIVE: To further evaluate the roles of matrix metalloproteinase 1 (MMP-1), MMP-3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the pathogenesis of joint inflammation and articular erosions in early inflammatory arthritis. METHODS: Untreated patients with joint symptoms for <2 years were evaluated at presentation and followed up prospectively for 18 months. Swollen joint count and serum levels of C-reactive protein (CRP) were determined every 6 months. Serum levels of MMP-1, MMP-3, and TIMP-1 were measured by double-antibody sandwich enzyme-linked immunosorbent assay at the same time intervals. The number of joint erosions in serial radiographs of the hands and feet was also recorded. Analysis of synovial fluid levels of MMPs and TIMP-1 at presentation was completed in some patients. RESULTS: Of 175 patients evaluated at baseline, 85 had rheumatoid arthritis (RA), 39 had seronegative spondylarthropathy, 38 had undifferentiated arthritis, and 13 had self-limiting arthritis. Of 164 patients with available radiographs of the hands and feet at presentation, 33 (20.1%) had joint erosions. Baseline levels of MMP-1, MMP-3, and TIMP-1 were significantly higher (P = 0.0001, P = 0.013, and P = 0.0001, respectively) and ratios of TIMP-1:MMP-1 and TIMP-1:MMP-3 were significantly lower (P = 0.0001 and P = 0.013, respectively) in RA versus non-RA patients. In RA patients, serum levels of CRP correlated with MMP-3 and TIMP-1 levels, but not with MMP-1 levels. The number of erosions at presentation correlated with baseline levels of both MMP-1 and MMP-3, but not with levels of TIMP-1. One hundred one patients were followed up for the next 18 months. The number of patients with erosions and the number of erosions per patient increased significantly during this period. Area under the curve (AUC) measurements of MMP-1 and TIMP-1 levels, but not of MMP-3 levels, yielded significantly higher values in RA than in non-RA patients. In RA patients, only the AUC level of MMP-3 correlated with the AUC CRP level (r = 0.67, P = 0.0001), while only the AUC level of MMP-1 correlated with the number of new joint erosions (r = 0.28, P = 0.034). CONCLUSION: These data suggest an uncoupling of the pathophysiologic mechanisms associated with joint inflammation and articular erosion. Treatments that inhibit the production and activity of MMP-1 may preferentially limit the formation of new joint erosions and improve the long-term functional outcome of some patients with inflammatory arthritis.

Adolescent↗
PubMed2003

Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction.

OBJECTIVE: Degradation of the collagenous extracellular matrix by metalloproteases (MMPs) plays an important role in the pathogenesis of osteoarthritis (OA). Recently, it was suggested that endothelin 1 (ET-1), a potent vasoconstrictor, may be involved in MMP regulation. This study investigated the role of ET-1 in OA cartilage degradation. METHODS: We explored ET-1 expression and synthesis in normal and OA cartilage and synovial membrane by reverse transcription-polymerase chain reaction and immunohistochemistry. MMP-1 and MMP-13 gene expression and protein synthesis were investigated using Northern blotting and enzyme-linked immunosorbent assays. Additionally, ET-1-induced collagenase activity, type II collagen metabolites, and tissue inhibitor of metalloproteases 1 (TIMP-1) protein were evaluated. RESULTS: We found expression and synthesis of ET-1, in situ, in both normal and OA cartilage and synovial membrane. We demonstrated that ET-1 induced gene expression and protein synthesis of both MMP-1 and MMP-13. These enzymes were produced in OA chondrocyte cultures, and the production increased in a dose-dependent manner in the presence of ET-1. In OA cartilage, ET-1 also induced type II collagen-derived neoepitopes concomitantly with an increase in collagenase activity and a decrease in TIMP-1 protein. CONCLUSION: Our results provide strong evidence of the catabolic role of ET-1 in OA cartilage via MMP-1 and MMP-13 up-regulation. As well, ET-1 increased the net MMP/TIMP balance and secondarily increased collagen degradation. Hence, ET-1 becomes an attractive factor to target in the conception of new therapeutic approaches for OA and other diseases in which MMP-13 and MMP-1 actions are crucial in tissue alteration.

Adult↗
PubMed2007

Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.

OBJECTIVE: To explore the involvement of synovial macrophages in early cartilage damage in osteoarthritis (OA), and to identify the role of matrix metalloproteinase 3 (MMP-3) in the pathology of early and late OA. METHODS: The role of synovial macrophages in MMP-mediated damage in OA was studied by depleting synovial macrophages prior to elicitation of a collagenase-induced instability model of OA. The expression of MMP in synovium and cartilage was monitored using TaqMan analysis. In spontaneous and induced OA, cartilage pathology was scored in MMP-3-knockout mice and control mice, by histologic assessment and VDIPEN staining. RESULTS: On day 14 following induction of OA, MMP-mediated neoepitopes were detected in cartilage from mice with mild experimental OA (mean +/- SD positively stained surface area 20 +/- 3.2%). Remarkably, by depleting synovial macrophages prior to induction of OA, the generation of MMP-induced neoepitopes was largely prevented (mean +/- SD positively stained surface area 5 +/- 1%; P< 0.001), indicating an important role for synovial macrophages in the occurrence of MMP-mediated cartilage damage. We observed a strong decrease in MMP-3 and MMP-9 expression in synovial but not cartilage tissue in macrophage-depleted joints. Among 2-year-old mice, spontaneous OA-like changes in the lining layer were significantly decreased in MMP-3-knockout mice compared with control mice. Even more striking was the 67% reduction in the occurrence of severe cartilage damage in MMP-3-knockout mice. In addition, MMP-mediated VDIPEN expression was significantly decreased, indicating reduced MMP-mediated cartilage breakdown. CONCLUSION: The results of this study prove that MMP-3 is involved in the generation of severe cartilage damage in murine OA. Synovial macrophages are crucial in early MMP activity and appear to mediate MMP production in synovium rather than cartilage.

Animals↗
PubMed2002

Immunohistochemical expression of vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic lesions.

BACKGROUND: Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, plays a hierarchical role in regulating physiologic and pathologic angiogenesis. Moreover, the transformation from noninvasive to invasive carcinomas is accompanied by focal disruption and discontinuity of the basement membrane. Several groups of proteases have been implicated in tumor cell invasion, including the 72-kDa gelatinase A/Type IV collagenase (matrix metalloproteinase 2 [MMP-2]) and the 92-kDa gelatinase B/Type IV collagenase (MMP-9). METHODS: The authors assessed the immunohistochemical expression of VEGF and metalloproteinases MMP-2 and MMP-9 in paraffin embedded biopsy specimens of malignant melanomas (18 invasive melanomas and 10 in situ melanomas); dysplastic nevi with architectural disorder and cytologic atypia of melanocytes; Spitz nevi; and compound or predominantly intradermal, ordinary, benign melanocytic nevi. RESULTS: Strong cytoplasmic staining for VEGF was observed in melanoma cells in as many as 77% of primary invasive melanomas, whereas only 25% of the in situ melanomas exhibited a detectable immunoreactivity for VEGF. It is interesting to note that no immunoreactivity was shown by any nevi; Spitz nevi, in particular, showed negative immunoreactivity to VEGF. Invasive melanomas and in situ melanomas displayed coexpression of MMP-2 and MMP-9, although to a variable extent. In particular, high MMP-2 staining was observed in 14 of 18 invasive melanomas; moreover, strong MMP-2 expression also was observed in 60% of in situ melanomas, whereas the residual 40% of those melanomas showed a moderate level of positivity. CONCLUSIONS: On the basis of the current data showing that malignant melanocytic tumors displayed strong VEGF expression, whereas benign melanocytic proliferations showed no immunoreactivity for VEGF, VEGF also may be used as a discriminating factor to distinguish malignant melanoma from lesions of uncertain histology.

Dysplastic Nevus Syndrome↗
PubMed2003

Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase-2 (gelatinase A) without inhibiting its activation.

BACKGROUND: In the current study, the authors investigated the effects of synthetic low molecular weight inhibitors of matrix metalloproteinases (MMPs) on the expression and activation of MMP-2 in a three-dimensional tissue system. METHODS: Rabbit periosteal explants were cultured with or without various concentrations of the MMP inhibitors CT1166, CT1399, or CT1746, and conditioned media and tissue extracts were analyzed for the expression and activity of MMP-2. RESULTS: The data showed that blocking the activity of all MMPs with relatively high inhibitor concentrations completely prevented the conversion of pro-MMP-2 into its active form and that the level of protein was decreased. Selective inhibition of the activity of gelatinases (MMP-2 and MMP-9) by using low inhibitor concentrations, however, induced a higher level of active MMP-2 and increased its expression significantly. CONCLUSIONS: The current observations indicate that selective inhibitors of MMPs affect the expression and activity of MMP-2, thus providing clues regarding the differing effects such inhibitors appear to have when applied in vivo.

Animals↗
PubMed1997

Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers.

We have previously reported increased expression of matrix metalloproteinase-2 (MMP-2) using a rat model of liver fibrosis. However we did not clarify how the precursor of MMP-2 (proMMP-2) was activated. Therefore, we used human liver specimens with chronic hepatitis (CH) and liver cirrhosis (LC) to examine expression of membrane-type-1-MMP (MT1-MMP), which has recently been determined to activate proMMP-2. Northern hybridization studies showed a 5.4- and 1.4-fold increase in MMP-2 expression in CH and LC, respectively, as compared with normal liver. MT1-MMP gene expression simultaneously increased 4.0- and 1.4-fold in CH and LC, respectively. In situ hybridization using 35S-cRNA probes of MMP-2 and MT1-MMP showed prominent silver granules in elongated cells found in the lobules, periportal areas, and fibrous septa of CH and LC samples. These elongated cells expressed alpha-smooth muscle actin by immunohistochemistry. Immunoelectron microscopic examination localized MMP-2 and MT1-MMP to the rough endoplasmic reticulum of stellate cells located in the lobules and periportal areas, or to fibroblasts in the fibrous septa, suggesting that MMP-2 and MT1-MMP were produced by these cells. In addition, cytoplasmic and membranous immunodeposits of both MMPs were found in endothelial cells, Kupffer cells, capillary endothelial cells, and lymphocytes, indicating that activation of proMMP-2 occurs locally. Increased expression of MMP-2 and MT1-MMP was detected in CH and LC, while dual over-expression was found in stellate cells and fibroblasts, possibly resulting in the increase of active MMP-2 in and around these cells. These findings suggest that activated MMP-2 may remodel liver parenchyma during the process of liver fibrosis.

Adult↗
PubMedDate not supplied

Limited processing of pro-matrix metalloprotease-2 (gelatinase A) overexpressed by transfection in PC-3 human prostate tumor cells: association with restricted cell surface localization of membrane-type matrix metalloproteinase-1.

The expression and activation of matrix metalloproteinases (MMPs) by tumor cells is correlated with progression to invasive and metastatic status. The purpose of this study was to examine the role of increased MMP-2 (gelatinase A) expression in prostate cancer progression utilizing human prostate PC-3 cancer cells that overexpress MMP-2 using gene transfection. PC-3 cells were transfected with pCR-3 vector only and pCR-3 MMP-2 plasmids employing the LipofectAMINE method, and stable transfectants were selected with G418. The expression of MMP-2, tissue inhibitor of metalloproteinase-2 (TIMP-2), and membrane-type MMP 1 (MT1-MMP) in PC-3 parental and transfected cells under serum-free conditions was determined by zymography, immunoblotting, immunofluorescent microscopy, Northern blotting, and/or reverse transcriptase-polymerase chain reaction (RT-PCR). MMP-2 transfected cells produced primarily the proenzyme form of MMP-2; the parental and vector control transfected PC-3 cells did not express any MMP-2 that was detectable by the methods we employed. Treatment of PC-3 MMP-2 transfected cells with Concanavalin A (Con A), in contrast to HT-1080 cells, processed only a small amount of the secreted 72-kd proenzyme to a 62-kd intermediate and a cell-associated 59-kd active form. The low level of secreted pro-MMP-2 processing induced by Con A was inhibited by serine protease inhibitors and was unaffected by cyclic adenosine monophosphate (cAMP). Immunoblotting showed that these cells produced abundant TIMP-2 and lower amounts of MT1-MMP in comparison with Con A-responding HT-1080 cells. HT-1080 cells respond to Con A by translocating MT1-MMP from intracellular localization sites to the plasma membrane, an effect not observed in PC-3 cells. The molecular basis for the low level of processing of pro-MMP-2 by PC-3 cells may be due to an overabundance of TIMP-2 and/or a low level of cell surface active MT1-MMP.

Blotting, Northern↗
PubMed2002

Plasmin activates pro-matrix metalloproteinase-2 with a membrane-type 1 matrix metalloproteinase-dependent mechanism.

Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been implicated as a physiological activator of progelatinase A (MMP-2). We previously reported that plasmin treatment of cells results in proMMP-2 activation and increased type IV collagen degradation. Here, we analyzed the role of MT1-MMP in plasmin activation of MMP-2 using HT-1080 cells transfected with MT1-MMP sense or antisense cDNA. Control, vector-transfected cells that expressed endogenous MT1-MMP, and antisense cDNA transfectants with very low levels of MT1-MMP did not activate proMMP-2. Conversely, cells transfected with sense MT1-MMP cDNA expressed high MT1-MMP levels and processed proMMP-2 to 68/66-kDa intermediate activation products. Control cells and MT1-MMP transfectants had much higher levels of cell-associated MMP-2 than antisense cDNA transfectants. Addition of plasmin(ogen) to control or MT1-MMP-transfected cells generated active, 62-kDa MMP-2, but was ineffective with antisense cDNA transfectants. The effect of plasmin(ogen) was prevented by inhibitors of plasmin, but not by metalloproteinase inhibitors, implicating plasmin as a mechanism for proMMP-2 activation independent of the activity of MT1-MMP or other MMPs. Plasmin-mediated activation of proMMP-2 did not result from processing of proMT1-MMP and did not correlate with alpha(v)beta(3) integrin or TIMP-2 levels. Thus, plasmin can activate proMMP-2 only in the presence of MT1-MMP; however, this process does not require the catalytic activity of MT1-MMP.

DNA, Complementary↗
PubMed2007

Regulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases by Porphyromonas gingivalis in an engineered human oral mucosa model.

Under physiological conditions, matrix metalloproteinases (MMPs) are involved in the remodeling and turnover of periodontal tissue and their activity is tightly regulated by tissue inhibitors of metalloproteinases (TIMPs). Disturbances in the balance between MMPs and TIMPs may result in excessive tissue destruction. We previously used an engineered human oral mucosa (EHOM) model to demonstrate that Porphyromonas gingivalis, a major etiological agent of periodontitis, infiltrates connective tissue and induces significant loss of attachment of the stratified epithelium from the basement membrane. The aim of the present study was to investigate the effect of P. gingivalis on the expression and production of MMP-2, MMP-9, TIMP-1, and TIMP-2 by oral fibroblasts and epithelial cells. The EHOM model was infected with P. gingivalis ATCC 33277 or its derivative gingipain-null mutant (KDP128) for different periods of time. MMP and TIMP mRNA expression was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) analysis, while protein secretion into the culture medium was assessed by enzyme-linked immunosorbent assays. P. gingivalis significantly up-regulated MMP-2 and MMP-9 mRNA expression by oral epithelial cells. This MMP gene activation was paralleled by TIMP-2 gene activation. However, only MMP-9 mRNA expression was significantly enhanced by the gingipain-null mutant. At 8 and 24 h post-infection, P. gingivalis increased significantly the MMP-9 protein level compared to the uninfected EHOM model. The present study reports the ability of P. gingivalis to regulate MMP and TIMP production by oral cells, a phenomenon that may contribute to tissue destruction.

Gene Expression Regulation, Enzymologic↗
PubMed1992

Interactions between HIV-infected monocytes and the extracellular matrix: increased capacity of HIV-infected monocytes to adhere to and spread on extracellular matrix associated with changes in extent of virus replication and cytopathic effects in infected cells.

Monocytes express cell surface receptors for extracellular matrix (ECM) proteins of basement membranes. These receptors are engaged during extravasation of cells through capillary endothelium into tissue. The number of human immunodeficiency virus (HIV)-infected monocytes that adhered to ECM over 2 h was threefold higher than that of uninfected control cells. This difference was ECM specific and was not observed with a bovine serum albumin substrate. Enhanced adhesion to ECM was evident in monocytes by 4 days after HIV infection and increased through 10 days. Monocytes exposed to a T cell-tropic HIV strain that binds to but does not replicate in monocytes showed no changes in adherence to ECM. Thus, productive infection of monocytes by HIV induces a significant increase in the capacity of these cells to interact with ECM. Enhanced adhesion of HIV-infected monocytes to ECM was associated with increased spreading: at 12 h, sixfold more HIV-infected monocytes were spread on ECM than were uninfected control cells. Cell processes of HIV-infected monocytes formed a complex network on ECM: many of these cells expressed HIV proteins as detected by indirect immunofluorescence. HIV-associated cytopathic effects and levels of virion-associated reverse transcriptase activity depended on the substrate to which monocytes were attached. Virus replication and cytopathic effects in monocytes adhered to ECM, fibronectin, or plastic alone were comparable. In contrast, HIV-infected monocytes attached to laminin showed a significant increase in virus replication and in extent of cytopathic effects through 2 weeks after infection. The lowest levels of HIV replication and cytopathic effects were in monocytes attached to collagen IV. Interactions between monocytes and ECM profoundly affect the manner in which these cells control HIV infection: HIV infection changes the capacity of infected monocytes to attach and spread on ECM; attachment to ECM alters the extent of virus replication in infected cells.

Cell Adhesion↗
PubMed2002

Stimulation of matrix metalloproteinase-9 expression in human fibrosarcoma cells by synthetic matrix metalloproteinase inhibitors.

Enhanced expression and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with beta-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as Il-1beta and TNF-alpha were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-spectrum MMPIs.

Collagen Type IV↗
PubMed2002

IL-18 initiates release of matrix metalloproteinase-9 from peripheral blood mononuclear cells without affecting tissue inhibitor of matrix metalloproteinases-1: suppression by TNF alpha blockage and modulation by IL-10.

The proinflammatory cytokine interleukin (IL)-18 appears to be involved in the etiology of a variety of pathological conditions, among them rheumatoid arthritis and atherosclerosis as well as tumor growth and metastasis. As biological activity of matrix metalloproteinase-9 (MMP-9) has been identified as a hallmark in the pathogenesis of these diseases, effects of IL-18 on MMP-9 production by human peripheral blood mononuclear cells (PBMC) were investigated. Moreover, effects of immunopharmacological intervention by anti-tumor necrosis factor-alpha (TNFalpha) or IL-10 were evaluated. Here we report that IL-18 augmented production of MMP-9 by PBMC. The potency of IL-18 to induce release of MMP-9 from PBMC was comparable with that of TNFalpha. MMP-9 production was dependent on endogenous production of TNFalpha, as detected by use of neutralizing monoclonal antibodies. Whereas IL-18 and TNFalpha induced the protease, MMP-9 release was not mediated by IFNgamma. IL-18 also induced secretion of MMP-9 from human whole blood cultures. Antiinflammatory IL-10 efficiently downregulated release of MMP-9 from unstimulated and IL-18-activated PBMC. In contrast to MMP-9, secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) was not augmented by IL-18. Addition of IL-10 enhanced release of TIMP-1 from PBMC. The present study broadens the current pattern of IL-18 proinflammatory actions on PBMC, emphasizes the pivotal role of intermediate TNFalpha production in these responses, and relates IL-18 biological functions to the pathological role of MMP-9.

Gene Expression Regulation↗
PubMed2006

Altered plasma matrix metalloproteinase-9/tissue inhibitor of matrix [corrected] metalloproteinase-1 concentration during the early postoperative period in patients with colorectal cancer.

BACKGROUND: The authors have previously demonstrated that insulin-like growth factor binding protein-3 (IGFBP-3) is depleted in plasma for 1 to 3 days after major open surgery (OS), but not after laparoscopic surgery (LS). After surgery, IGFP-3 cleavage occurs rapidly and is likely attributable to altered plasma proteolytic activity. This study aimed to assess plasma proteolysis after both open and closed colorectal resection and, if possible, to identify a protease/protease inhibitor system affected by surgery. METHODS: Plasma from 88 patients with colorectal cancer (stages I-III) who underwent resection was obtained preoperatively (pre-OP) and on postoperative days (POD) 1 to 3. Plasma proteolytic activity was assessed via zymography. On the basis of the results, specific protease and protease inhibitor concentrations were next measured via enzyme-linked immunoassay (ELISA). Statistical analysis was performed using Wilcoxon's test. RESULTS: Early after surgery, zymography showed a predominant band representing a 92-kDa gelatinase corresponding to a proform of matrix metalloproteinase-9 (MMP-9), a protease known to cleave IGFBP-3. In OS patients, the mean concentration of plasma MMP-9 was significantly higher on POD 1 than at pre-OP (p < 0.003). On POD 2 and 3, no differences were noted. In the LS group, the mean levels of MMP-9 before and after surgery were comparable. The levels of a natural MMP-9 inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), also were measured. In the OS group, the level of TIMP-1 was significantly higher on POD 1 (p < 0.0003) and POD 2 (p < 0.01) and 3 (p < 0.01) than at pre-OP. In the LS group, a smaller but significant increase in TIMP-1 levels was found between the pre-OP sample and the POD 1 (p < 0.01) and POD 2 (p < 0.01) samples. No difference was noted on POD 3 (p = 0.1). CONCLUSIONS: Open surgery, but not laparoscopic surgery, is accompanied by a short-lived significant increase in MMP-9 levels, which likely accounts for the decrease in IGFBP-3 levels observed after OS. The transitory nature of MMP-9 imbalance may be attributable to the increase in TIMP-1 levels postoperatively.

Adenocarcinoma↗
PubMed2006

Urinary levels of matrix metalloproteinase 9 and 2 and tissue inhibitor of matrix metalloproteinase in patients with coronary artery disease.

OBJECTIVES: To evaluate the feasibility of an assay for urinary levels of matrix metalloproteinases (MMPs) and the potential usefulness of urinary MMPs as a marker of coronary atherosclerosis or acute coronary syndromes (ACS). METHODS AND RESULTS: We measured urine and plasma MMP-9, MMP-2 and urine tissue inhibitor of metalloproteinase (TIMP-1) in patients with ACS (n=27), patients with coronary artery disease (CAD), but no clinical instability (n=47) and a group of healthy volunteers (n=15) who were <35 years of age, had no risk factors for CAD and did not undergo angiography. Compared with volunteers, patients with ACS and CAD had higher urine MMP-9, urine TIMP-1, plasma MMP-9 and plasma MMP-2 levels, but these did not differ between those with CAD and ACS. Using the volunteers to roughly establish an upper limit of normal, 84% of the urine TIMP-1 values and 95% of the urine MMP-9 values were abnormally elevated among those with CAD and ACS. CONCLUSIONS: Urine MMP-9 and TIMP-1 levels are elevated in patients with CAD and ACS compared with healthy volunteers. A high percent of patients with CAD or ACS had elevated urine values of MMP-9 and TIMP-1 suggesting these variables might be a useful marker of atherosclerotic disease.

Acute Disease↗
PubMed2005

Difference in expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in patients with persistent ovarian cysts.

Matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9 expression with real-time quantitative polymerase chain reaction were analyzed in endometriotic and nonendometriotic ovarian cysts. Although MMP-1 was not detected, MMP-9 and MMP-2 were expressed in all of the cysts. In particular, in five of six nonendometriotic cysts (83.3%) MMP-2 expression was higher than in endometriotic cysts. These data may represent new molecular elements helpful in differential diagnosis of endometriotic lesions.

Chronic Disease↗
PubMed2006

Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury.

The objective of this study was to assess matrix metalloproteinase (MMP) and MMP inhibitor expression in the airspace of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and to determine the prognostic significance of MMP expression in this patient population. Twenty-eight patients with ALI or ARDS were prospectively enrolled in this study; bronchoalveolar lavage (BAL) fluid obtained from these patients was examined for expression of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-8 (neutrophil collagenase), and MMP-9 (gelatinase B). Levels of MMP inhibitors (ie, tissue inhibitor of metalloproteinases-1 and -2 [TIMP-1 and TIMP-2]) were examined in parallel. Expression of MMPs was correlated with relevant clinical outcomes in patients with ALI/ARDS. In nearly all specimens obtained from patients with ALI/ARDS, there were high levels of MMP-2, MMP-8, MMP-9, and TIMP-1, but in only a small subset of patients (6/28) were there detectable levels of MMP-1 and/or MMP-3. In the patients with elevated MMP-1 and/or MMP-3, the mortality rate was higher (83%) than in the group without detectable levels of these enzymes (32%). Likewise, the overall severity of disease as indicated by Acute Physiology and Chronic Health Evaluation III scores was higher in this group (98 +/- 30) than in the group without detectable MMP-1 or MMP-3 (78 +/- 28). The percentage of individuals in whom lung disease was complicated by multiorgan failure was also higher in the group with detectable MMP-1 and/or MMP-3 (83%) than in the group without (64%), as was the number of organs that failed. In contrast, there was no correlation between MMP-1 and/or MMP-3 expression and impairment in gas exchange, as determined by the ratio of partial pressure of oxygen to fraction of inspired oxygen (Pao(2)/Fio(2)) on the day of BAL sample. Based on these findings, we conclude that elevated MMP-2, MMP-8, and MMP-9 in BAL fluid is a marker of acute lung injury (and, perhaps, a contributor to ALI) but is not necessarily an indicator of a poor outcome. On the other hand, the presence of detectable MMP-1 and/or MMP-3 is an indicator of more ominous disease progression.

Bronchoalveolar Lavage Fluid↗
PubMed2005

Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma.

To successfully establish a metastasis from an invasive carcinoma, the first step involves the degradation of the underlying basement membrane, which is mainly made up of type IV collagen. Matrix metalloproteinases (MMPs)-2 and -9 are thought to play an important role in its degradation because of their ability to destroy this type of collagen. In order to evaluate the prognostic significance of these proteases, we studied the expression of MMP-2 and -9 in series of 68 OSCC by immunohistochemistry. Of the oral carcinomas, 28% (n = 19) expressed MMP-2, and 17.6% (n = 12) expressed MMP-9. MMP-2 immunoreactivity was significantly higher in patients with alcohol consumption (p = 0.028) (OR = 4), and in those younger than 60 years (p = 0.041). MMP-9 immunostaining showed statistically significant association with the tumor grade of differentiation (p = 0.019), the T-stage (p = 0.05), and also with the alcohol intake (p = 0.04) (OR = 7.67). In the present study, although not statistically significant, we observed that immunoexpression of MMP-2 and MMP-9 was stronger in patients with lymph node metastasis (OR = 1.65 and 2.29, respectively). In patients without regional lymph node metastasis, positive MMP-9 immunostaining was related to poor survival rates (p = 0.02; OR = 5.8). MMP-2 and -9 are involved in the invasion process of oral cancer, and MMP-9 is related to poor prognosis in the subset of patients without neck node metastasis. Ethanol could enhance the carcinogenetic process in oral cavity through its influence in the expression of MMP-2 and -9.

Adult↗