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At least 19 recordsLinked to original sources
PubMed1999

Expression of membrane type 1 matrix metalloproteinase, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 in human cartilaginous tumors with special emphasis on mesenchymal and dedifferentiated chondrosarcoma.

Membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as an activator of the proenzyme of matrix metalloproteinase 2 (MMP-2: gelatinase A), and has also been shown to play a crucial role in tumor invasion by activating proMMP2 in both lung and gastric carcinoma. The tissue inhibitor of metalloproteinase 2 (TIMP-2) plus the MT1-MMP complex also plays an important role in the activation of proMMP-2. In this study, the expressions of MT1-MMP, MMP-2 and TIMP-2 were evaluated in 10 enchondromas, 34 conventional chondrosarcomas, 5 clear-cell chondrosarcomas, 7 mesenchymal chondrosarcomas and 8 dedifferentiated chondrosarcomas. The expressions were immunohistochemically visualized on paraffin sections and the levels of expression were assessed semiquantitatively. The extent of staining was assessed by the extent score in order to determine the overall level of expression. The extent scores of MT1-MMP, MMP-2 and TIMP-2 in grade 2 chondrosarcoma were significantly higher than those in either enchondroma or grade 1 chondrosarcoma (P < 0.05). In conventional chondrosarcoma, significant correlations were found between the extent scores of MT1-MMP and MMP-2 (P < 0.001), MT1-MMP and TIMP-2 (P < 0.01), and MMP-2 and TIMP-2 (P < 0.01). The undifferentiated small round tumor cells of mesenchymal chondrosarcoma showed lower positive rates and extent scores for MT1-MMP (2/7, 0.7 +/- 0.5) and MMP-2 (3/7, 0.7 +/- 0.4) than for cartilaginous components of mesenchymal chondrosarcoma [MT1-MMP (4/7, 1.3 +/- 0.5) and MMP-2 (7/7, 1.9 +/- 0.3)] or conventional chondrosarcoma. In dedifferentiated chondrosarcoma, the extent scores of MT1-MMP, MMP-2 and TIMP-2 in low-grade cartilaginous components were not significantly different from those in conventional chondrosarcoma; however, the high-grade anaplastic components showed high extent scores for MT1-MMP, MMP-2 and TIMP-2, compared with the low-grade cartilaginous components of dedifferentiated chondrosarcoma or conventional chondrosarcoma. According to our results, the expression of MT1-MMP as well as that of MMP-2 or TIMP-2 demonstrated a significant correlation with the tumor grade in human cartilaginous tumors. Furthermore, the expressions of MT1-MMP, MMP-2 and TIMP-2 were also found to play a crucial role in invasion in the high-grade components of dedifferentiated chondrosarcoma.

Bone Neoplasms↗
PubMed2002

Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck.

BACKGROUND: Numerous reports have documented a direct involvement of matrix metalloproteinase (MMP) overexpression in the development and progression of head and neck squamous cell carcinoma (HNSCC). In this study, the authors examined whether the expression of MMPs in HNSCC is correlated with other steps involved in tumor growth and metastasis, like angiogenesis, activation the nitric oxide (NO) pathway, and alteration of the p53 tumor suppressor gene. METHODS: MMP-1, MMP-2, and MMP-9 expression levels were examined immunohistochemically in samples from 43 patients with HNSCC. Microvessel density (MVD) was determined by immunostaining of endothelial cells with anti-CD31 monoclonal antibody. Inducible nitric oxide synthase (iNOS) activity and cyclic guanosine monophosphatate (cGMP) levels were assessed in fresh tumor samples, whereas exons 5-9 of the p53 gene were analyzed by reverse transcriptase-polymerase chain reaction, single-strand conformation polymorphism analysis and were sequenced. RESULTS: MMP-1 overexpression (>10% of tumor cells) was identified in 32 tumors (74.5%), whereas elevated levels of MMP-2 and MMP-9 were detected in 17 tumors (39.5%) each. Tumors with MMP-9 overexpression were characterized by significantly higher MVD (P = 0.05) and significantly higher iNOS activity and cGMP levels (P = 0.005 and P = 0.02, respectively). Moreover, p53 mutation was associated strongly with MMP-9 overexpression (P = 0.004). Conversely, no correlation was found between MMP-1 and MMP-2 expression, angiogenesis, iNOS activity, cGMP levels, and p53 mutation in this series. CONCLUSIONS: This study documents the existence of a correlation between MMP-9 expression, activity of the iNOS pathway, p53 status, and angiogenesis in patients with HNSCC. This raises the possibility that p53 mutation, which frequently is present in HNSCC, may result in increased angiogenesis and invasiveness related to increased nitric oxide and MMP production by tumor cells, ultimately contributing to tumor progression.

Carcinoma, Squamous Cell↗
PubMed2005

Increased expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and matrix metalloproteinase-13 in lesional skin of bullous pemphigoid.

BACKGROUND: Matrix metalloproteinase (MMP)-2, MMP-9 and MMP-13 can degrade type IV collagen which is the major component of the basement membrane zone (BMZ). In bullous pemphigoid (BP), the separation occurs within the BMZ. OBJECTIVE: To evaluate the involvement of MMPs in the pathogenesis of BP, we examined the expression of MMP-2, MMP-9 and MMP-13 in the lesional skin of BP patients. METHODS: The expression of MMP-2, MMP-9, MMP-13, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 was analyzed by immunohistochemistry in the lesional skin of BP patients in comparison with that in normal human skin. Next, the cellular sources of MMP-2, MMP-9 and MMP-13 were analyzed by double immunohistochemistry. Finally, the levels of these MMPs in the serum and blister fluid of BP patients were measured by ELISA. RESULTS: The number of cells expressing MMP-2, MMP-9 and MMP-13 were significantly increased in the lesional skin of BP patients as compared to that in normal skin. Although the number of cells expressing TIMP-1 and TIMP-2 were also increased in the lesional skin of BP patients as compared to that in normal skin, the ratio of MMPs to TIMPs in the lesional skin of BP patients was high (2.4:1). T cells comprised the major source of MMP-2, MMP-9 and MMP-13, while a proportion of mast cells and eosinophils also expressed these MMPs. Furthermore, marked expression of MMP-2 was detected in the epidermal keratinocytes. The levels of these MMPs in the blister fluid were significantly greater than those in the serum. CONCLUSION: These results suggest that MMP-2, MMP-9 and MMP-13 may be involved in the mechanism of blister formation in BP and that besides infiltrating inflammatory cells, structural cells like epidermal keratinocytes may also participate in the induction of blister formation in BP.

Aged↗
PubMed2006

The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg ulcers.

INTRODUCTION: Alteration in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase-2 (MMP-2), tissue inhibitors of matrix metalloproteinases (TIMP-2) and platelet derived growth factor (PDGF-AA) may contribute to poor healing in venous leg ulcers. AIM: The aim of this study is to determine the expression of EMMPRIN, MMP-2, TIMP-2 and PDGF-AA in the ulcer exudates and perivascular tissue of healing and non-healing chronic venous ulcers. PATIENTS, MATERIALS AND METHODS: Forty patients with chronic venous ulcers were included in this study, with a mean age of 60 years. Eleven patients were males and 29 were females. All patients had normal ankle brachial index and a venous ulcer of at least 8 weeks duration. Immuno-histochemistry using monoclonal antibodies to PDGF-AA, MMP-2, TIMP-2 and EMMPRIN was carried out on paraffin embedded punch biopsy skin specimens from the ulcer edge. Enzyme linked immunosorbent assay for PDGF, MMP-2 and TIMP-2 were carried out on wound fluids collected from patients. The ulcer size and character at the initial assessment and after 8 weeks were assessed to determine the status of ulcer healing. RESULTS: No significant difference was seen in the expression of TIMP-2, MMP-2 and EMMPRIN between the two groups. However, in the non-healing group high levels of MMP-2 and low levels of TIMP-2 in the wound fluid suggest a strong correlation of these two markers in the state of healing. Analysis of wound fluid by ELISA demonstrated high PDGF-AA in the healing group (p = 0.021). Significantly increased levels of PDGF-AA (p<0001) was noted in the perivascular area on immuno-histochemistry of healing ulcers. These data suggest that PDGF-AA plays an important role in healing of venous ulcers. CONCLUSION: Non-healing venous ulcers are associated with greater activity MMP-2 activity. The ratio of MMPs to their inhibitors TIMPs, dictate the rate of healing of the ulcers. PDGF-AA activity is associated with ulcer healing, though the mechanism is unclear. EMMPRIN expression in chronic venous ulcers probably parallels the chronicity of the condition rather than propagate it. However, further studies with larger samples are needed.

Basigin↗
PubMed1999

Increased expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 with tumor dedifferentiation in hepatocellular carcinomas.

Destruction of the extracellular matrices is required for tumor invasion and metastasis. Matrix metalloproteinase-2 degrades type IV collagen and laminin, major components of the basement membrane. Membrane type 1 matrix metalloproteinase activates the latent form of matrix metalloproteinase-2. We studied changes in membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 expression in relation to the tumor differentiation of hepatocellular carcinomas. Activity of matrix metalloproteinase-2 was also evaluated in hepatocellular carcinomas and noncancerous tissues. Overall, 37 hepatocellular carcinomas were studied. Expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 was determined by either immunohistochemistry (n=37) or in situ hybridization (n=6). Changes in membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 expression were evaluated in relation to tumor differentiation. Gelatinolytic activities were analyzed by gelatin zymography (n=4). Membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 were detected in hepatoma cells and stromal cells. In addition, these matrix metalloproteinases were detected in the same hepatoma cells. Increased expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 was associated with tumor dedifferentiation. The active form of matrix metalloproteinase-2 was more strongly expressed by hepatocellular carcinomas than by noncancerous tissues. These findings indicate that increased expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 was associated with tumor dedifferentiation, suggesting that these matrix metalloproteinases are intimately involved in the invasion of hepatocellular carcinomas.

Adult↗
PubMed2002

Long-term overexpression of membrane type-1 matrix metalloproteinase and matrix metalloproteinase-2 in oleic acid-induced pancreatitis in rats.

INTRODUCTION: The matrix metalloproteinase (MMP) plays important roles in extracellular matrix turnover. However, little is known about the roles of MMP-2 and type IV collagen, and the relationship between MMP-2 and membrane type-1 matrix metalloproteinase (MT1-MMP) during progressive destruction of acinar cells in pancreatitis. AIMS AND METHODOLOGY: To examine the serial changes in the expression and activity of MMP-2 and expression of MT1-MMP and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in rats after induction of pancreatitis by intraductal infusion of oleic acid, and to determine protein concentrations by Western blot analysis and localization of type IV collagen by immunostaining. RESULTS: Gelatinolytic activity of pro-and active MMP-2 and concentrations of MT1-MMP protein, as determined by zymography and Western blot analysis, respectively, increased significantly from 6 hours to day 42 after intraductal infusion of oleic acid. TIMP-2 mRNA expression was significantly higher than that at time 0 throughout the study period, and gelatinolytic activity of active MMP-2 increased from day 3 to day 42. In addition, immunoreactivity for type IV collagen was detected as a discontinuous line along the basement membranes of ducts, vessels, tubular complexes, and acinar cells. CONCLUSION: Our findings indicate that long-term increases of gelatinolytic activity of active MMP-2 cause continuous disorganization of type IV collagen in basement membranes during progressive atrophy of pancreatic gland in oleic acid-induced pancreatitis, and that MT1-MMP and TIMP-2 work as activating factors during proMMP-2 activation. Moreover, basement membranes disorganization in the sustentacula of acinar cells and duct epithelia seems to participate in continuous derangement of acinar cells and duct epithelium.

Animals↗
PubMed2006

Coordinated elevation of membrane type 1-matrix metalloproteinase and matrix metalloproteinase-2 expression in rat uterus during postpartum involution.

BACKGROUND: The changes occurring in the rodent uterus after parturition can be used as a model of extensive tissue remodeling. As the uterus returns to its prepregnancy state, the involuting uterus undergoes a rapid reduction in size primarily due to the degradation of the extracellular matrix, particularly collagen. Membrane type-I matrix metalloproteinase (MT1-MMP) is one of the major proteinases that degrades collagen and is the most abundant MMP form in the uterus. Matrix metalloproteinase-2(MMP-2) can degrade type I collagen, although its main function is to degrade type IV collagen found in the basement membrane. To understand the expression patterns of matrix metalloproteinases (MMPs) in the rat uterus, we analyzed their activities in postpartum uterine involution. METHODS: We performed gelatin zymography, northern blot analysis and immunohistochemistry to compare the expression levels of MT1-MMP, MMP-2, matrix metalloproteinase-9 (MMP-9) and the tissue inhibitors of MMPs-1 and 2 (TIMP-1 and TIMP-2) in the rat uterus 18 h, 36 h and 5 days after parturition with their expression levels during pregnancy (day 20). RESULTS: We found that both MT1-MMP and MMP-2 localized mainly in the cytoplasm of uterine interstitial cells. The expression levels of MT1-MMP and MMP-2 mRNAs and the catalytic activities of the expressed proteins significantly increased 18 h and 36 h after parturition, but at postpartum day 5, their mRNA expression levels and catalytic activities decreased markedly. The expression levels of MMP-9 increased 18 h and 36 h after parturition as determined by gelatin zymography including the expression levels of TIMP-1 and TIMP-2. CONCLUSION: These expression patterns indicate that MT1-MMP, MMP-2, MMP-9, TIMP-1 and TIMP-2 may play key roles in uterine postpartum involution and subsequent functional regenerative processes.

Animals↗
PubMed2002

Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer.

Preclinical studies have provided evidence that matrix metalloproteinases (MMPs), a family of zinc-containing proteolytic enzymes, facilitate tumor invasion, the establishment of metastases, and the promotion of tumor-related angiogenesis. Matrix metalloproteinase inhibitors (MMPIs) have been shown to inhibit tumor growth and dissemination in preclinical models. Not all lung cancers express the MMPs believed to be most important in promoting the neoplastic process, and there are conflicting reports regarding the prognostic significance of MMPs in lung cancer. However, it is possible that these observations are because of limitations in the procedures for measuring MMPs. Many investigators believe that MMPs are universally involved in tumor progression; this hypothesis was the basis for initiating seven phase III MMPI trials in lung cancer. Four studies were closed at completion of the predefined accrual goal, and three were closed early. There were no significant differences in survival in a non-small cell lung cancer prinomastat study, and in a small cell lung cancer marimastat trial. The results of the remaining five studies have not been reported. At this point it appears that MMPIs will probably not play a major role in the treatment of advanced lung cancer patients.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Clinical significance of expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 in human head and neck squamous cell carcinoma.

Three different membrane-type matrix metalloproteinases (MT-MMPs) activate in vitro the latent form of matrix metalloproteinase-2 (MMP-2), which is one of the key proteinases in invasion and metastasis of various cancers. We examined the mRNA expression of MT1, 2, and 3-MMPs and MMP-2 in cell lines of head and neck squamous cell carcinoma (HNSCC) and quantitated the relative expression levels in human HNSCC tissues by Northern blotting. The tissue localization of MT1-MMP and MMP-2 was determined by immunohistochemistry and in situ hybridization. Their implications in clinicopathologic factors were statistically evaluated. All cell lines examined consistently expressed MT1-MMP and MMP-2, but not MT2, 3-MMP. In the clinical specimens, there was a significant correlation in coexpression of messenger of RNA (P = .0005) and colocalization by immunohistochemistry (P < .0001) for MT1-MMP and MMP-2. Relative mRNA expression levels of MT1-MMP and MMP-2 in the carcinoma tissues were significantly higher than those of the control tissues (P = .0045 and P = .0122, respectively). Both mRNA expression level and immunopositivity of MT1-MMP significantly correlated with lymph node metastasis (P = .0081 and P = .0193, respectively), which was confirmed by multivariate logistic regression analysis. Immunoreaction of MT1-MMP and its mRNA expression were observed in both carcinoma cells and stromal cells. The localization of MMP-2 closely corresponded to that of MT1-MMP. These observations suggest that MT1-MMP possesses a role as a determinant of lymph node metastasis in HNSCC, and that concurrent expression of MT1-MMP and MMP-2 are involved in progression of HNSCC.

Blotting, Northern↗
PubMed2006

Matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: study based on an enzyme-linked assay and immunohistochemical staining.

BACKGROUND: Various glomerular diseases progress to end-stage renal failure due to an accumulation of the mesangial matrix (MM) and a thickening of the glomerular basement membrane (GBM). Both the MM and GBM are consistently metabolized through the synthesis and destruction of the matrix. Such synthesis is influenced by transforming growth factor-beta (TGF-beta) and other factors, whereas the destruction is presumed to be mediated by both matrix metalloproteinases (MMPs) and inhibitors of matrix metalloproteinases (TIMPs). Based on such evidence, we tried to detect MMP-2, MMP-9, and TIMP-1 in the peripheral blood of patients with various glomerular diseases. METHODS: Serum was used to detect MMP-2 and TIMP-1, while plasma was used to detect MMP-9. These enzymes were detected using an enzyme-linked assay. RESULTS: The findings showed an increased level of MMP-2 in patients with a alteration of GBM, typically membranous nephropathy (MN), regardless of the differences in their etiological processes. In contrast, MMP-9 did not show a strong association with any specific glomerular abnormalities. However, it mainly tended to increase in patients with MM accumulation. In addition, the localization of MMP-2, MMP-9, and TGF-beta1 was studied using immunohistochemical staining. MMP-2 was demonstrated to exist in the glomerular capillary loop (GCL) as well as in the mesangial cells and the mesangial matrix. MMP-9 was found to exist in mesangial cells and the matrix, GCL, infiltrated neutrophils, and some tubular epithelial cells. Positive staining for TGF-beta1 in GCL was found to be associated with an increased level of MMP-2 in patients with MN, whereas in MM such positive staining was not necessarily associated with an increased level of MMP-9. CONCLUSIONS: These results therefore suggest that MMP-2 plays an important role in the degradation of GBM, while MMP-9 only moderately affects the degradation of MM.

Enzyme-Linked Immunosorbent Assay↗
PubMed1999

Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the intrauterine compartments during early pregnancy.

Matrix metalloproteinases (MMPs) are important enzymes in tissue remodelling, a key event for the development of the fetal membranes and placenta and establishing the feto-maternal interface during early pregnancy. This study has examined the secretion of the gelatinases, MMP-2 (72 kDa) and MMP-9 (92 kDa), and the endogenous tissue inhibitors of metalloproteinases (TIMPs) into extra-embryonic coelomic and amniotic fluids, the two principal intra-uterine compartments of the first trimester, and compared them to amniotic fluid collected later in gestation. In extra-embryonic coelomic fluid, gelatin zymography demonstrated that MMP-2 (72 kDa) was the predominant gelatinase, with some MMP-9 present. A broad range of TIMPs corresponding to TIMP-1 and TIMP-2, glycosylated and unglycosylated TIMP-3 and TIMP-4 was detected in this compartment by reverse zymography and immunoblot analyses. There was little gelatinase or TIMP activity in amniotic fluid in the first trimester. In amniotic fluid from the second trimester after fusion of the membranes obliterating the extra-embryonic coelom, and at term elective caesarean section, MMP-2 is the predominant gelatinase present, with a broad spectrum of TIMPs. These findings demonstrate that predominantly MMP-2 and also MMP-9, regulated by a range of TIMPs, are involved in intra-uterine tissue remodelling during the establishment of pregnancy.

Adult↗
PubMed2003

The triterpenoid CDDO inhibits expression of matrix metalloproteinase-1, matrix metalloproteinase-13 and Bcl-3 in primary human chondrocytes.

A synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), has been reported to have anti-inflammatory properties and to decrease the interleukin-1 (IL-1)-induced expression of matrix metalloproteinase-1 (MMP-1) and MMP-13. We have shown previously that IL-1 induces expression of the inhibitor of NF-kappaB (IkappaB) family member Bcl-3, and that this contributes to MMP-1 expression. To quantify the effects of CDDO on IL-1-induced MMP-1, MMP-13 and Bcl-3 expression, we stimulated the chondrosarcoma cell line SW-1353 and human primary chondrocytes with IL-1, in the presence or absence of CDDO. Harvested RNA was subjected to quantitative real-time reverse-transcriptase polymerase chain reaction. In SW-1353 cells, 300 nM CDDO significantly decreased the induction of MMP-1 and MMP-13 by IL-1. In human primary chondrocytes, 300 nM CDDO inhibited the induction of these genes by IL-1 to an even greater extent. In both cell types, inhibition of MMP-1 required 24 hours of pretreatment with CDDO, whereas MMP-13 could be inhibited when CDDO and IL-1 were added simultaneously to culture. In human primary chondrocytes, IL-1-induced Bcl-3 expression was inhibited when cells were pretreated with CDDO. To determine whether the inhibitory effect of CDDO on MMP worked through inhibition of Bcl-3 gene expression, SW-1353 cells stably transfected with a Bcl-3 expression plasmid were treated with IL-1 and/or CDDO, and MMP gene expression was assayed. Overexpression of Bcl-3 increased MMP-1, but not MMP-13, mRNA levels. Furthermore, overexpressed Bcl-3 could sustain the CDDO-dependent inhibition of IL-1-induced MMP-1 expression. Our data demonstrate that CDDO inhibits IL-1-induced MMP-1 and MMP-13 expression in human chondrocytes. CDDO also inhibits the expression of Bcl-3, an IL-1-responsive gene that preferentially contributes to MMP-1 gene expression.

B-Cell Lymphoma 3 Protein↗
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↗
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↗
PubMed2002

Influence of transforming growth factor-alpha on expression of matrix metalloproteinase-2, matrix metalloproteinase-9, and epidermal growth factor receptor gene in the mouse blastocysts.

PURPOSE: This study was carried out to investigate the influence of transforming growth factor-alpha (TGF-alpha) on the expression of mRNA for matrix metalloproteinase-2 (MMP-2), MMP-9, and epidermal growth factor receptor (EGFR) in mouse blastocysts and the effect on the production and activation of MMP-2 and MMP- 9 during blastocyst outgrowth. METHODS: Two-cell mouse embryos were cultured for 96 h in the presence or absence of various concentrations of TGF-alpha. Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of mRNA for MMP-2, MMP-9, and EGFR in in vitro cultured blastocysts. To investigate the effect on the production and activation of MMP-2 and MMP-9 during blastocyst outgrowth, the conditioned medium collected after 3 and 5 days of embryo culture were assayed for MMP activity by gelatin zymography. RESULTS: The relative mRNA levels of MMP-2 and MMP-9 in blastocysts treated with TGF-alpha were higher than that of the control in a concentration-dependent manner. The relative mRNA level of EGFR in blastocysts treated with TGF-alpha was higher than that of the control. In conditioned medium collected after 3 days of embryo culture, TGF-alpha induced the gelatinase activities of proMMP-9 in all groups and activated MMP-2 in the 10 and 100 ng/mL TGF-alpha treated groups. In conditioned medium collected after 5 days, TGF-alpha induced the gelatinase activities of proMMP-9 in all groups and activated MMP-9 in the TGF-alpha treated group. TGF-alpha also induced the gelatinase activities of activated MMP-2 in the 1 and 10 ng/mL TGF-alpha treated groups and the control. CONCLUSIONS: These results suggest that the addition of TGF-alpha to in vitro culture medium is proper to create a favorable environment for preimplantation embryo development and implantation.

Animals↗
PubMed2005

Expression of nm23-H1 gene product in sarcomatous cancer cells of renal cell carcinoma: correlation with tumor stage and expression of matrix metalloproteinase-2, matrix metalloproteinase-9, sialyl Lewis X, and c-erbB-2.

OBJECTIVES: To investigate the clinical significance of nm23-H1 gene product in sarcomatous cancer cells, because this is known as a tumor-metastasis suppressor. Renal cell carcinoma with sarcomatoid cancer cells is characterized by high malignant potential and a poor prognosis. METHODS: We investigated the expression of nm23-H1 gene product in the carcinomatous and sarcomatous component (CC and SC) of renal cell carcinoma using immunohistochemical techniques and the relationships between the expression and clinicopathologic features. We also examined the expression of matrix metalloproteinase (MMP)-2, MMP-9, sialyl Lewis X, and c-erbB-2 in the SC because these proteins are regulated by the nm23-H1 gene or its products. RESULTS: We examined 20 renal cell carcinoma specimens that contained an SC and CC. The CC of 12 of the 20 tumors stained positively for nm23-H1 gene product. In contrast, the SC of only 3 of the 20 stained positive. The reduced expression of nm23-H1 gene product in the SC correlated significantly with tumor invasion (P <0.01), but not with tumor size or metastasis. In contrast, the expression of the nm23-H1 gene product in the CC was not associated with these pathologic features. Expression of the nm23-H1 gene product correlated negatively with MMP-2 expression (r = -0.48, P = 0.03). Other factors did not show such significant correlations with nm23-H1 gene product expression. CONCLUSIONS: Our results suggest that low expression of nm23-H1 gene products may play important roles in tumor invasion, and that this process is mediated in part by overexpression of MMP-2.

Aged↗
PubMed2005

Circulating matrix metalloproteinase-2 but not matrix metalloproteinase-3, matrix metalloproteinase-9, or tissue inhibitor of metalloproteinase-1 predicts outcome in patients with congestive heart failure.

BACKGROUND: Extracellular matrix remodeling is thought to play an important role in the progression of heart failure (HF). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are matrix-degrading enzymes that have been demonstrated to influence left ventricular properties and serve as targets of potential anti-remodeling agents. Herein we evaluated the potential significance of circulating MMP and TIMP levels in patients with congestive HF (CHF) speculating it may assume prognostic value. METHODS: Serum samples were obtained from 88 consecutive patients attending the outpatient HF clinic and analyzed for MMP-2, -3, -9, and TIMP-1 as well as N-terminal probrain natriuretic peptide (NT-ProBNP). Patients were followed up for the occurrence of either mortality or hospitalizations due to CHF or either of each. RESULTS: Circulating levels of MMP-2, -9, and TIMP-1 but not of MMP-3 were increased in patients with CHF as compared with age-matched controls. Only MMP-2 and NT-ProBNP levels correlated significantly with New York Heart Association class. Matrix metalloproteinase-2 and NT-ProBNP levels did not correlate. Patients with circulating MMP-2 above 352 ng/mL were 4.2 times more likely to die, 2.2 times more likely to be hospitalized because of CHF, and 2.3 times more likely to experience either of the 2 end points as compared with patients with MMP-2 concentrations below this threshold. Both MMP-2 and NT-ProBNP were found to be independent predictors of mortality over a 24-month follow-up period. CONCLUSIONS: Matrix metalloproteinase-2 but not MMP-3, -9, or TIMP-1 serum levels is an independent predictor of mortality in patients with CHF.

Adult↗