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Results for “Matrix Metalloproteinase 2”

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PubMed2005

Matrix metalloproteinase 2 secretion in WEHI 164 fibrosarcoma cells is nitric oxide-related and modified by morphine.

Matrix metalloproteinases (MMP) are ubiquitous enzymes involved in extracellular matrix remodeling, and as a consequence in a number of physiological and pathological states, including development, wound healing and cancer. A crucial feature of cancer progression and metastasis is the disruption of extracellular matrix, and spreading of proliferating cancer cells. Modulation of MMP is a main target of cancer research. Using the mouse fibrosarcoma cell line WEHI 164, producing high amounts of MMP-2, we investigated whether we could modulate its production. We report that MMP-2 is under the control of nitric oxide (NO)/nitric oxide synthase (NOS) system. In addition, we show that NOS activity is controlled by opioids in a non-opioid receptor-related manner. Finally, we provide evidence that morphine, when administrated at low, non-toxic concentrations (<10(-9) M) attenuates MMP-2 activity. We conclude that, as morphine is able to decrease metalloproteinase activity via the NO/NOS system, it may have a place in the treatment of several sarcomas including fibrosarcoma.

Animals↗

PubMedDate not supplied

Expression of basement membrane antigens and matrix metalloproteinases 2 and 9 in cutaneous basal and squamous cell carcinomas.

BACKGROUND: Basement membrane (BM) antigens and matrix metalloproteinases (MMP) are involved in tumor invasion and metastasis. Basal (BCC) and squamous cell carcinomas (SCC) differ with respect to their biological behavior since the former are only locally aggressive whereas the latter have a metastatic potential. MATERIALS AND METHODS: We studied the immunohistochemical expression of several BM antigens and of MMP2 and MMP9, in 13 BCC, 13 SCC, and 8 in situ skin carcinomas. RESULTS: The expression of most BM antigens was reduced in the tumors in comparison with normal skin. Hemidesmosome- and lamina lucida-associated antigens (plectin, NUT2, alpha 6/CD49f and laminin-5) were more decreased in BCC, whereas collagens type VII and IV were more decreased in SCC as compared with BCC; in BCC and SCC both collagens tended to be decreased on the leading edge of invasive tumor masses. In situ carcinomas showed a slightly diminished expression of alpha 6/CD49f integrin, plectin and NUT2. The expression of both MMP2 and MMP9 was increased in SCC as compared with BCC. CONCLUSION: Our findings further upheld the role of BM antigens and MMPs in the process of tumor aggressiveness. The reduced expression of collagen IV, combined with an increased expression of both MMP2 and MMP9 could account for the increased metastatic potential of SCC vs BCC through an increased invasion of the extracellular matrix and the vascular space.

Antigens, Neoplasm↗

PubMed2004

Matrix metalloproteinase 2 is associated with changes in steroid hormones in the sera and peritoneal fluid of patients with endometriosis.

OBJECTIVE: To determine matrix metalloproteinase 2 (MMP-2) levels in sera and peritoneal fluids of women with or without endometriosis-associated infertility and to determine whether MMP-2 had correlation with 17beta-E(2) and P in the sera and peritoneal fluids of the patients with endometriosis. DESIGN: A case-control study. SETTING: A women's hospital in China. PATIENT(S): Forty patients with endometriosis-associated infertility undergoing laparoscopy and 18 women undergoing tubal ligation. INTERVENTION(S): Sera and peritoneal fluids were collected from women with or without endometriosis. MAIN OUTCOME MEASURE(S): Matrix metalloproteinase 2, 17beta-E(2), and P concentration. RESULT(S): Compared with the control women, the patients with endometriosis had higher MMP-2 levels in their sera and peritoneal fluids. Serum and peritoneal fluid MMP-2 levels were higher in the proliferative phase than in the secretory phase. The level of MMP-2 in the patients was correlated positively with 17beta-E(2) in serum and peritoneal fluid and negatively with P. CONCLUSION(S): The results demonstrated a correlation between MMP-2 concentrations and steroid hormones in sera and peritoneal fluids of the patients with endometriosis-associated infertility. Estradiol might up-regulate MMP-2, resulting in the formation of endometriosis. Progesterone might down-regulate MMP-2 to inhibit the formation and development of endometriosis.

Adult↗

PubMedDate not supplied

Matrix metalloproteinases 2 and 9 and their tissue inhibitors in low malignant potential ovarian tumors.

OBJECTIVES: This study aimed to analyze the expression of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and their tissue inhibitors TIMP-1 and TIMP-2 in low malignant potential (LMP) ovarian tumors and to compare these values with those recorded for benign and malignant ovarian neoplasms. METHODS: A total of 53 ovarian tumors (16 benign, 15 LMP and 22 malignant) were evaluated by immunohistochemistry for the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2. RESULTS: MMP-2 expression was found in 56% of the benign, 40% of the LMP, and 90% of the malignant ovarian tumors (benign vs. malignant, p = 0.021; LMP vs. malignant, p = 0.002). The expression of MMP-9, TIMP-1 and TIMP-2 was lower in the benign and LMP tumors compared with the malignant ones. CONCLUSION: The data suggest that, in relation to the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2, LMP ovarian tumors are more similar to benign than to malignant ovarian tumors.

Female↗

PubMed2006

Plasma concentration and activity of matrix metalloproteinase 2 and 9 in patients with breast disease, breast cancer and at risk of developing breast cancer.

Matrix metalloproteinases (MMPs) are involved in extracellular matrix modification and associated with invasive and metastatic behavior of human malignant tumors. Specifically, MMP2 and MMP9 are implicated in both early and late processes of tumor development. It is reported that MMPs occur as inactive precursors, active enzymes or enzyme inhibitor complexes in biological samples. However, there is limited knowledge on the role of each form in disease and/or the significance of changes in the plasma concentration and/or activity in breast cancer patients. The aim of this study was to determine if patients with breast cancer, benign disease and at risk for developing breast cancer display characteristic levels of active and/or total MMP2 and MMP9 in plasma. Concentration and activity of MMP2 and MMP9 were determined quantitatively in the plasma of 124 female volunteers diagnosed with breast cancer (n=31), benign disease (n=38), or determined by the Gail Model to be at high risk (n=31) or low risk (controls, n=24) of developing breast cancer. Data obtained was statistically analyzed to search for differences/patterns characteristic of each category. Concentration of total MMP2 was significantly lower in control individuals than benign, high risk (P<0.001 respectively) and breast cancer patients (P=0.002). Activity of total MMP2 was significantly lower in controls compared to cancer, benign and high risk patients (P<0.001 respectively). Attempts to build a predictive/descriptive model using canonical discriminant analysis (utilizing all eight features; concentrations and activity levels of active/total MMP2 and MMP9) enabled the distinction of the controls from the high risk, benign and cancer groups. Our results suggest that preoperative plasma concentration and activity of MMP2 and MMP9 may permit sub-classification of female patients with breast disorders.

Adult↗

PubMed2003

[Expression of matrix metalloproteinase 2 and 9 in liver tissue of patients with schistosomiasis japonica].

OBJECTIVE: To explore the change of matrix metalloproteinase-2(MMP-2) and matrix metalloproteinase-9 (MMP-9) expression in liver tissue of the patients with schistosomiasis japonica. METHODS: Liver biopsy materials were examined pathomorphologically in 26 patients with schistosomiasis in advanced stage and 5 cases without the disease as control. The expression of MMP-2, MMP-9 and C-IV were studied by immunohistochemistry, and result was analyzed by picture quantitative analysis technique. RESULTS: Immnoreactive MMP-2 was mainly expressed in the plasma, the membrane of hepatocytes and hepatic sinusoids, it was also found in myofibroblast cells and endothelial cells of blood vessel. Immnoreactive MMP-9 was observed in hepatic stellate cells, sinusoids and myofibroblast cells, sometimes it was also seen in the plasma of hepatocytes and epithelial cells of bile duct. The expression of MMP-2, MMP-9 and C-IV was significantly stronger in patients with advanced schistosomiasis than that of the control(P < 0.05). The expression of MMP-2 was relevant to the inflammation grade and stage of liver fibrosis(P < 0.01). The expression of MMP-9 did not show significant change(P > 0.05) and the expression of C-IV was consistent with that of MMP-2. CONCLUSION: The study indicates that increased expression of MMP-2 participated in the initiation and development process of liver fibrosis, MMP-9 was related to the initiation of liver fibrosis and pathological change existed in hepatic sinusoids in advanced schistosomiasis japonica.

Adult↗

PubMed2000

Enhanced urinary gelatinase activities (matrix metalloproteinases 2 and 9) are associated with early-stage bladder carcinoma: a comparison with clinically used tumor markers.

Matrix metalloproteinases (MMPs) are involved in tumor growth and metastasis, promoting the migration and invasion of cells. In this study, the amount of MMP-2 and MMP-9 activity was measured in urine from superficial bladder carcinoma patients (pTa, pT1) to evaluate their possible diagnostic value. The active and total amount of MMP-2 and MMP-9, respectively, in urine from tumor patients were compared with the levels in urine from age- and gender-matched healthy volunteers. Both MMP-2 and MMP-9 activity levels were significantly enhanced in urine from patients with high invasive cancers (pT2, PT3), whereas in urine from healthy controls no or very low MMP activities were found. More importantly, a substantial number of urine samples from patients with superficial tumors contained elevated MMP-2 and MMP-9 activities, suggesting that enhanced urinary MMP activity levels, indeed, might be indicative for early-stage bladder cancer. Overall, urinary MMP-2 and MMP-9 activity levels were significantly correlated to each other, with some individual exceptions. A comparison between urinary MMP-9 activity and a recently proposed urinary marker for bladder cancer, NMP-22, showed slightly lower numbers of patients with elevated levels for MMP-9. But because MMP-9 and NMP-22 levels were not correlated, enhanced urinary MMP activity might be useful as a marker for superficial bladder carcinoma like, or especially in combination with, other markers.

Adult↗

PubMedDate not supplied

Matrix metalloproteinases 2 and 9 in follicular fluids of patients undergoing controlled ovarian stimulation for ICSI/ET.

The objective of this study was to detect the level of matrix metalloproteinases 2 and 9 in the follicular fluid of patients undergoing controlled ovarian stimulation and to correlate these levels with hormonal and clinical parameters. Follicular fluids were collected from thirty patients participating in an intracytoplasmic sperm injection/embryo transfer (ICSI/ET) program in "Otmar Bauer" Assisted Reproduction Center, Alexandroupolis, Greece. Follicular fluid was collected at oocyte retrieval and MMP-2 and MMP-9 were identified by gelatin zymography. Gelatin zymography of the follicular fluids revealed bands consistent with proMMP-2 and proMMP-9. ProMMP-2 was the predominant band in the majority of samples. The levels of MMPs varied considerably among the samples. A significant positive correlation between MMP-2 and the peak estradiol levels was found.

Adult↗

PubMed2005

Urokinase increases the content and activity of matrix metalloproteinases 2 and 9 during in vivo constrictive arterial remodeling.

Perivascular application of urokinase to ballooned artery stimulating the formation of neointima and constrictive arterial remodeling increased the content and activity of matrix metalloproteinases 2 and 9 in vivo. Application of recombinant tissue plasminogen produced no such changes. It was demonstrated that urokinase stimulates expression of matrix metalloproteinases in vivo.

Angioplasty, Balloon↗

PubMed2003

Systemic arterial expression of matrix metalloproteinases 2 and 9 in acute Kawasaki disease.

OBJECTIVE: Coronary artery aneurysms are the major complication of Kawasaki disease (KD). Matrix metalloproteinases (MMPs) regulate remodeling and degradation of the extracellular matrix. We hypothesized that MMP-9 expression is increased in acute KD aneurysms when compared with KD nonaneurysmal arteries and arteries from control children. METHODS AND RESULTS: MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were immunolocalized in coronary arteries from children with fatal acute KD and controls. In KD coronary aneurysms, MMP-2 expression was prominent in the thickened neointima and in endothelial cells of new capillaries in areas of angiogenesis. MMP-9 was absent in control coronary arteries but was expressed in coronary artery aneurysms, nonaneurysmal coronary and noncoronary arteries, and cardiac nerves in acute KD, without an increase in TIMP-1 expression. CONCLUSIONS: MMP-2 likely participates in remodeling of the arterial wall in acute KD, particularly in the processes of neointimal proliferation and angiogenesis. MMP-9 may play a role in the development of coronary aneurysms, but its expression is not confined to aneurysmal arteries. Systemic arterial expression of MMP-9 in acute KD, even in the absence of inflammatory changes in the vessel, suggests induction by a circulating factor, or possibly by an infectious agent with tropism for arterial tissue.

Acute Disease↗

PubMed2006

Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation.

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma.

Amino Acid Sequence↗

PubMed2000

Interaction with heparin and matrix metalloproteinase 2 cleavage expose a cryptic anti-adhesive site of fibronectin.

We recently found that fibronectin (FN) had a functional site [YTIYVIAL sequence in the heparin-binding domain 2 (Hep 2)] that was capable of suppressing the integrin-mediated cell adhesion to extracellular matrix. However, our results also indicated that this anti-adhesive site seemed to be usually buried within the Hep 2 domain structure because of its hydrophobic nature, raising a question as to the physiological significance of the cryptic anti-adhesive activity of FN. The present study demonstrates that the cryptic anti-adhesive activity can be exposed through the physiological processes. A 30-kDa chymotryptic FN fragment derived from Hep 2 domain (Hep 2 fragment), which had no effect on adhesion of MSV-transformed nonproducer 3T3 cell line (KN(7)8) to FN, expressed the anti-adhesive activity after treatment with 6 M urea. Light scattering and circular dichroism measurements showed that the urea treatment induced the conformational change of the Hep 2 fragment from a more compact form to an unfolded one. Incubation of the Hep 2 fragment with heparin also induced similar conformational changes and expression of anti-adhesive activity. Additionally, both the urea and heparin treatments made the Hep 2 fragment and intact FN much more accessible to the polyclonal antibody (alphaIII14A), with a recognition site near the anti-adhesive site of FN. Specific cleavage of either the Hep 2 fragment or intact FN by matrix metalloproteinase 2 (MMP-2) released a 10-kDa fragment with the anti-adhesive activity, which was shown to have the exposed anti-adhesive site on the amino-terminal region. Thus, the cryptic anti-adhesive activity of FN can be expressed upon conformational change and proteolytic cleavage of Hep 2 domain.

3T3 Cells↗

PubMed2002

Nitric oxide induces gelatinase A (matrix metalloproteinase 2) during rat embryo implantation.

OBJECTIVE: To evaluate a reciprocal signaling interaction initiated by embryo-derived nitric oxide (NO) to facilitate implantation by increased production of gelatinase A (matrix metalloproteinase 2, MMP2) in uterine stroma. DESIGN: Experimental animal studies. SETTING: Reproductive-physiology research laboratory. ANIMAL(S): Female syngeneic Wistar rats aged 14 weeks. INTERVENTION(S): Vaginal smears to confirm pregnancy. Oviductal ligature to avoid the descent of blastocysts to the uterine lumen. Plasma exudation assays to locate uterine blastocyst implantation sites. Organ cultures treated with NO donors and nitric oxide synthase (NOS) inhibitors. MAIN OUTCOME MEASURE(S): Expression of MMP2 and NO was assessed by Western blot and zymography of tissue extracts and by immunofluorescence of tissue sections. RESULT(S): An increase in MMP2 activity was found in uterine extracts in early pregnant rats and was concentrated at implantation sites. Immunolocalization experiments showed that inducible NOS was expressed on the surface of the implanting blastocyst adjacent to the uterine epithelium at the sites of increased MMP2 expression. In organ culture experiments, NO donors were found to increase, whereas NOS inhibitors were found to decrease MMP2 activity in uterine tissue sections. CONCLUSION(S): Blastocyst-derived NO contributes to the production of uterine-derived MMP2, an essential component of implantation and initiation of placentation.

Animals↗

PubMed2005

Matrix metalloproteinase 2 and 9 expression correlated with cavernous sinus invasion of pituitary adenomas.

OBJECT: Matrix metalloproteinase (MMP) 2 and 9 are important for tissue breakdown in the process of tumor invasion. The aim of this study is to evaluate the relationship between the expression of MMP-2, MMP-9, MIB-1 LI and cavernous sinus invasion in pituitary adenomas. METHODS: Tissue samples from 54 patients with pituitary adenomas were studied. Expression of MMP-2, MMP-9, and MIB-1 labeling index (LI) were evaluated by immunohistochemical method. In sixteen cases, the expression of MMP-2 and MMP-9 mRNA was also examined by RT-PCR assay. RESULTS: Thirty-four patients were women and 20 were men, with a mean age of 49.9 years old (range 18-76 years). There were 12 cases with cavernous sinus invasion, and 42 were noninvasive cases. MMP-2 and MMP-9 score of invasive case (3.9 +/- 0.5,4.1 +/- 0.4) were significantly higher than those (2.3 +/- 0.2; p < 0.01; 2.6 +/- 0.2; p < 0.01) without invasion. The MIB-1 LI of this study presented no significantly difference between the invasive and noninvasive pituitary adenomas. The percentage of MMP-2 mRNA/beta-actin mRNA and MMP-9 mRNA/beta-actin mRNA were also observed significantly higher in invasive pituitary adenomas (68.2 +/- 15.3%; 59.7 +/- 12.5%) than noninvasive pituitary adenomas (21.8 +/- 8.2%, p < 0.05; 33.3 +/- 5.4%, p < 0.05). CONCLUSIONS: Our study suggests that the expression of MMP-2 and MMP-9 may have a value to assess the invasive pituitary adenomas, and proliferation and invasion of pituitary adenomas may present a different mechanism.

Adenoma↗

PubMed1996

Characterization of gelatinases linked to extracellular matrix invasion in ovarian adenocarcinoma: purification of matrix metalloproteinase 2.

Substantial evidence indicates that proteolytic degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Our previous work has demonstrated elevated secretion by cultured ovarian adenocarcinoma cells of two gelatinolytic metalloproteinases, a 72-kDa enzyme resembling matrix metalloproteinase 2 (MMP-2) and a 92-kDa enzyme resembling MMP-9 (Moser et al, Int. J. Cancer 56, 552-559, 1994). To assess the potential in vivo relevance of these enzymes, we have examined ovarian carcinoma ascites using gelatin substrate zymography. MMP species identical to those secreted from several well-characterized ovarian adenocarcinoma cell lines were found in the majority of ascites: MMP-2-like gelatinase (23 of 23 cases) and MMP-9-like gelatinase (18 of 23 cases), suggesting a prevalence of these species in the ovarian carcinoma microenvironment and their availability for tumor-associated proteolysis. The contribution of these proteinases to ovarian cancer invasion was further demonstrated by experiments measuring tumor cell-mediated proteolysis of native endothelial cell extracellular matrix (ECM) and tumor cell invasion of reconstituted basement membrane (Matrigel). These data showed that secretion of type IV collagenase activity by a series of independently isolated ovarian adenocarcinoma cell lines correlated well with the ability of these cells to proteolyze the ECM and invade the basement membrane. Furthermore, we have identified and characterized an ovarian carcinoma-associated gelatinase, the 72-kDa MMP found in conditioned media of the DOV 13 cell line, as MMP-2. This enzyme was identical to the previously described MMP-2 from other sources by Western blot, amino terminal sequence, and substrate specificity. Additionally, a large portion of the MMP-2 activity found in DOV 13 conditioned media is active without organomercurial treatment, suggesting that ovarian cancer cells have an endogenous activator of the zymogen. Together, these data suggest that ECM proteolysis mediated by tumor-associated proteinases plays an important role in the invasion and/or metastasis of ovarian carcinoma.

Adenocarcinoma↗

PubMed1999

Expression of matrix metalloproteinases 2 and 9 in regenerating skeletal muscle: a study in experimentally injured and mdx muscles.

Matrix metalloproteinases (MMPs) cooperatively degrade all components of the extracellular matrix (ECM). Remodeling of ECM during skeletal muscle degeneration and regeneration suggests a tight regulation of matrix-degrading activity during muscle regeneration. In this study, we investigated the expression of MMP-2 and MMP-9, in normal muscles and their regulation during regeneration process. We further investigated their secretion by C2C12 myogenic cell line. Two models of muscle degeneration-regeneration were used: (1) normal muscles in which necrosis was experimentally induced by cardiotoxin injection; (2) mdx muscles which exhibit recurrent signs of focal myofiber necrosis followed by successful regeneration. MMPs were studied by zymography; their free activity was quantified using 3H-labeled gelatin substrate and mRNA expression was followed by Northern hybridization. Muscle degeneration-regeneration was analyzed by conventional morphological methods and in situ hybridization was performed on muscle sections to identify the cells expressing these MMPs. Results show that MMP-2, but not MMP-9 expression, is constitutive in normal muscles. Upon injury, the active form of MMP-2 is transiently increased, whereas MMP-9 is induced within 24 h and remains present for several days. Quantitative assays of free gelatinolytic activity show a progressive and steady increase that culminates at 7 days postinjury and slowly returns to normal levels. In adult mdx mice, both pro and active forms of MMP-2 and MMP-9 are expressed. Northern blot results support these findings. Zymography of C2C12-conditioned medium shows that myogenic cells produce MMP-2. By in situ hybridization we localized MMP-9 mRNA in inflammatory cells and putative activated satellite cells in injured muscles. Our data allow the correlation of the differential expression of pro and/or active forms of MMP-2 and MMP-9 with different stages of the degeneration-regeneration process: MMP-9 expression is related to the inflammatory response and probably to the activation of satellite cells, whereas MMP-2 activation is concomitant with the regeneration of new myofibers.

Animals↗

PubMed2003

Analgesic effect of intrathecally administered matrix metalloproteinase 2 (MMP-2) in the rat formalin test.

Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases that selectively degrade components of the extracellular matrix. In the present study, the authors examined the effect of intrathecal injection of MMP-2 on the nociceptive transmission during the rat formalin test (a model of inflammatory pain). The paw formalin injection induces biphasic flinching (phase 1: 0-6 min; phase 2: 10-60 min) of the injected paw. Intrathecal injection of 1 microg of MMP-2 depressed the phase 1 agitation behavior, but not the phase 2 agitation behavior, and this effect of MMP-2 was antagonized by ONO-4817, an MMP inhibitor. ONO-4817 itself had no effect on the formalin test. These data suggest that exogenously applied MMP-2 to the spinal cord produces analgesic effects in the rat formalin test.

Analgesics↗

PubMed1996

Matrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation.

A biologic role for the 72-kDa gelatinase A (matrix metalloproteinase 2; MMP-2), beyond simple extracellular matrix turnover, was evaluated in glomerular mesangial cells. To determine the significance of MMP-2 secretion for the acquisition of the inflammatory phenotype, we reduced the constitutive secretion of MMP-2 by cultured mesangial cells with antisense RNA expressed by an episomally replicating vector or with specific anti-MMP-2 ribozymes expressed by a retroviral transducing vector. The phenotype of the transfected, or retrovirally infected, cells was profoundly altered from the activated state and closely approximated that of quiescent cells in vivo. The prominent differences included a change in the synthesis and organization of the extracellular matrix, loss of activation markers, and a virtually total exit from the cell cycle. Reconstitution with exogenous active, but not latent MMP-2, induced a rapid return to the inflammatory phenotype in vitro. This effect was specific to MMP-2, because the closely related MMP-9 did not reproduce these changes. Furthermore, this pro-inflammatory effect of MMP-2 is dependent upon the active form of the enzyme, which can be produced by an autocatalytic activation process on the mesangial cell plasma membrane. It is concluded that MMP-2 acts directly upon mesangial cells to permit the development of an inflammatory phenotype. Specific inhibition of MMP-2 activity in vivo may represent an alternate means of ameliorating complex inflammatory processes by affecting the phenotype of the synthesizing cells, per se.

Animals↗