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PubMed2004

Large-scale and effective screening of Korean medicinal plants for inhibitory activity on matrix metalloproteinase-9.

Matrix metalloproteinase-9 (MMP-9) degrades type IV collagen constituting the major structural component of the basement membrane and extra cellular membrane. The enzymatic activity is found to be elevated in tumor tissues. With the aim of finding novel MMP-9 inhibitors from natural products, 87 extracts of oriental medicinal herbs, which are used as prescriptions for cancer treatment in traditional Korean medicine, were screened for their inhibitory activities towards MMP-9. It was found that most of the hexane and chloroform fractions as well as water extracts showed a weak inhibitory effect on MMP-9 activity at a concentration of 100mug/ml. However, a strong inhibition was found in the butanol fractions of Cinnamomum cassia PRESL, Magnolia obovata THUEB., Magnolia officinalis REHD. et WILS., Magnolia officinalis REHD. et WILS. var. biloba REHD. et WILS., and Euonymus alatus (THUNB.) SIEB. with inhibitory activity (>90%) at a concentration of 100 microg/ml.

Cell Line, Tumor↗
PubMed2003

Collagen of chronically inflamed skin is over-modified and upregulates secretion of matrix metalloproteinase 2 and matrix-degrading enzymes by endothelial cells and fibroblasts.

In order to investigate the properties of collagen in chronically inflamed tissue, we isolated collagen from the ear skin of mice with chronic contact dermatitis and examined its biochemical characteristics and the functions that regulate the secretion of matrix metalloproteinase 2 and collagen-degrading enzymes from endothelial cells and fibroblasts. Collagen in skin with chronic contact dermatitis comprised 60% type I collagen and 40% type III collagen, which latter is higher than the content of type III collagen in control skin (35%). The denaturation temperature was higher (42 degrees C) than that of control skin (39 degrees C). The alpha2 chain of type I collagen was over-hydroxylated at both proline and lysine residues. Segment-long-spacing crystallites of type I collagen were unusually connected in tandem. Collagen of chronically inflamed skin was less susceptible to matrix metalloproteinase 2 after heat denaturation. Endothelial cells and fibroblasts secreted an increased amount of matrix metalloproteinase 2 when cultured on a gel formed from the collagen of chronically inflamed skin. Collagen-degrading activity secreted from fibroblasts was also upregulated when cells were in contact with collagen of chronically inflamed skin. These results suggest that the collagen in chronically inflamed tissue has altered biochemical characteristics and functions, which may affect the pathogenesis of the chronic skin disease.

Animals↗
PubMed2003

Active immunogene therapy of cancer with vaccine on the basis of chicken homologous matrix metalloproteinase-2.

Matrix metalloproteinase (MMP) family, in particular MMP-2, may play a key role in angiogenesis and tumor growth. It is conceivable that the breaking of immune tolerance of MMP-2 should be a useful approach to cancer therapy by active immunity. To test this concept, we constructed a plasmid DNA encoding chicken homologous MMP-2 (c-MMP-2) and control vectors. We found that the vaccine based on chicken homologous MMP-2 as a model antigen could induce both protective and therapeutic antitumor immunity. Autoantibodies against MMP-2 in sera of mice immunized with c-MMP-2 could be found by Western blotting analysis and ELISA assay. There was the deposition of autoantibodies within the tumor. IgG1 and IgG2b were substantially increased in response to c-MMP-2 immunization. The elevation of MMP-2 in the sera of tumor-bearing mice was abrogated with the vaccination of c-MMP-2. Transmigration of human endothelial cells and tumor cells through gelatin-coated filters was inhibited with immunoglobulins isolated from mice immunized with c-MMP-2. The gelatinase activity of MMP-2, including both latent MMP-2 (M(r) 72,000) and active MMP-2 (M(r) 66,000) derived from tumor tissues, was apparently inhibited by the vaccination with c-MMP-2. The antitumor activity and the inhibition of angiogenesis were acquired by the adoptive transfer of the purified immunoglobulins. The antitumor activity and production of autoantibodies against MMP-2 could be abrogated by the depletion of CD4(+) T lymphocytes. Angiogenesis was apparently inhibited within tumor, and chick CAMs angiogenesis was also inhibited. Thus, our findings may provide a vaccine strategy for cancer therapy through the induction of an autoimmune response against MMP-2 in a cross-reaction by the immunization with the single xenogeneic homologous MMP-2 gene and may be of importance in the additional exploration of the application of other xenogeneic homologous genes identified in human and other animal genome projects in cancer therapy.

Animals↗
PubMed2006

Expression of matrix metalloproteinases 3, 10 and 11 (stromelysins 1, 2 and 3) and matrix metalloproteinase 7 (matrilysin) by cancer cells in non-small cell lung neoplasms. Clinicopathologic studies.

Matrix metalloproteinases (MMP's) 3, 10 and 11 (also known as stromelysins 1, 2 and 3, respectively), and matrix metalloproteinase 7 (also known as matrilysin), produced by stromal fibroblast-like cells in the vicinity of various malignancies, are suspected to have an ability to degrade components of extracellular matrix, thus promoting spread of the tumor. MMP's also have been found in epithelial tumor cells in various cancers. Tissue sections from 95 cases of non-small cell lung cancer (NSCLC) were immunostained with antibodies against MMP 3, MMP 10 and MMP 11 and sections from 99 cases of NSCLC were immunostained with an antibody against MMP 7. Cytoplasmic immunoreactivity in the tumor cells was semiquantitatively scored for intensity and distribution and correlated with tumor type, tumor grade, stage, tumor size, lymph node positivity, metastasis and survival. Overexpression of MMP 10 and MMP 11 correlated with higher grade for NSCLC (p = 0.029 and p = 0.016, respectively), and also in a subset of adenocarcinomas (AC) (p = 0.015 and p = 0.009, respectively). Also, MMP 10 and MMP 11 correlated with lymph node involvement in NSCLC (p = 0.025 and p = 0.027 respectively). No correlation was found for MMP 3. Overexpression of MMP-7 correlated with tumor stage (p = 0.0001) and was associated with adverse clinical outcome (p = 0.0001) in NSCLC and also in separate squamous cell carcinoma (SCC) (p = 0.003) and AC (p = 0.004) tumor groups.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Matrix metalloproteinase-2 in dentin matrix mineralization.

In the serum-free culture medium of bovine odontoblasts we detected active gelatinolytic metalloproteinases, matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinases A and B). The activity of MMP-2, in particular, appeared suddenly around day 21 in the culture, coinciding with the development of odontoblastic cell processes and the loss of alkaline phosphatase. Reverse transcriptase-polymerase chain reaction analysis of these odontoblasts demonstrated that messages of MMP-2 but not MMP-9 increased significantly between day 15 and day 21. The in vitro observation indicates that medium conditioned by these odontoblasts and containing significant amounts of MMP-2 degrades not only the collagenous substrates but also purified dentin phosphophoryn as well. We have also observed that dephosphorylated dentin phosphoprotein becomes a better substrate for casein kinase II after limited proteolysis with MMP-2. These results support our working hypothesis that MMP-2-mediated proteolytic processing is an important step in accelerating the process of dentin matrix maturation, which includes phosphorylation and subsequent mineralization. As has been suggested previously, extracellular phosphorylation of matrix proteins is an important step in biomineralization both in bone and in dentin (Mikuni-Takagaki et al., J Bone Miner Res 1995;10:231-42; Zhu et al., Biochem J 1997; 323:637-43). Our present histochemical analysis in MMP-2 knockout mice confirms the concept with the delayed formation of mineralized tissues, dentin, and bone.

Alkaline Phosphatase↗
PubMedDate not supplied

Expression of membrane-type matrix metalloproteinase in rabbit neointimal tissue and its correlation with matrix-metalloproteinase-2 activation.

Smooth muscle cell (SMC) phenotypic alteration, followed by migration and proliferation, is a prominent feature of atherogenesis and vascular neointimal formation. Despite extensive research, mechanism(s) responsible for this alteration remain unclear. Recently, matrix metalloproteinases (MMP), a family of potent proteinases, have been implicated in vascular diseases by way of extracellular matrix degradation. Of particular interest is that expression of a 72-kD MMP (MMP-2) is elevated in neointima, and inhibition of this MMP results in reduced SMC migration and proliferation, suggesting a role for MMP-2 in neointimal development. However, MMP-2 needs activation before digesting protein; the mechanism of this activation in the arterial wall is largely unexplored. A novel membrane-type MMP termed MT-MMP-1 has recently been identified, and its expression in tumor cells is concomitant with MMP-2 activation. Transfection of this MMP cDNA into mammalian cells results in activation of MMP-2. However, the importance of this MMP in various pathological situations is not clear. The present study was designed to explore the relationship between MT-MMP- 1 expression and MMP-2 activation during rabbit neointimal development. Using polymerase chain reaction, we isolated a rabbit cDNA from arterial SMC; sequence analysis indicated that it is a rabbit form ofMT-MMP-1. A segment of this cDNA was subcloned into pGEM-3 and employed to synthesize a DIG-labeled RNA probe. This probe was then used in the Northern blot analysis for MT-MMP-1 mRNA expression both in aortic tissue and in neointimal tissues developed 3, 7, 14 and 21 days after balloon catheter de-endothelialization. The results show low-level expression ofMT-MMP-1 in the normal aortic wall; expression is significantly increased in the neointimal tissues, with peak expression observed in tissues 3 days after injury. Expression of active MMP-2 was also determined using gel zymography. A close temporal expression pattern was observed between MT-MMP-1 and active MMP-2. These data verify the expression of MT-MMP-1 in arterial SMC and suggest its importance in MMP-2 activation after balloon catheter de-endothelialization.

Amino Acid Sequence↗
PubMed2006

Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells.

Proteolytic shedding is an important step in the functional down-regulation and turnover of most membrane proteins at the cell surface. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a multifunctional glycoprotein that has two Ig-like domains in its extracellular portion and functions in cell adhesion as an inducer of matrix metalloproteinase (MMP) expression in surrounding cells. Although the shedding of EMMPRIN is reportedly because of cleavage by metalloproteinases, the responsible proteases, cleavage sites, and stimulants are not yet known. In this study, we found that human tumor HT1080 and A431 cells shed a 22-kDa EMMPRIN fragment into the culture medium. The shedding was enhanced by phorbol 12-myristate 13-acetate and inhibited by TIMP-2 but not by TIMP-1, suggesting the involvement of membrane-type MMPs (MT-MMPs). Indeed, down-regulation of the MT1-MMP expression in A431 cells using small interfering RNA inhibited the shedding. The 22-kDa fragment was purified, and the C-terminal amino acid was determined. A synthetic peptide spanning the cutting site was cleaved by MT1-MMP in vitro. The cleavage site is located in the linker region connecting the two Ig-like domains. The N-terminal Ig-like domain is important for the MMP inducing activity of EMMPRIN and for cell-cell interactions, presumably through its ability to engage in homophilic interactions, and the 22-kDa fragment retained the ability to augment MMP-2 expression in human fibroblasts. Thus, the MT1-MMP-dependent cleavage eliminates the functional N-terminal domain of EMMPRIN from the cell surface, which is expected to down-regulate its function. At the same time, the released 22-kDa fragment may mediate the expression of MMPs in tumor tissues.

Amino Acid Sequence↗
PubMedDate not supplied

Coordinate expression of membrane type-matrix metalloproteinases-2 and 3 (MT2-MMP and MT3-MMP) and matrix metalloproteinase-2 (MMP-2) in primary and metastatic melanoma cells.

Expression of MMP-2 in melanoma cells has been demonstrated to be involved in the degradation of extracellular matrix during melanoma growth and to correlate with later melanoma metastasis. MMP-2 is considered to be activated by membrane-associated matrix metalloproteinases (MT-MMPs). To know whether MT-MMPs are involved in the activation of MMP-2 in melanoma cells, immunohistochemical studies were performed in primary and metastatic melanoma by use of the antibodies for MT1-MMP, MT2-MMP and MT3-MMP. Expression of MT1-MMP, MT2-MMP, MT3-MMP and MMP-2 in nevocellular nevus (n = 5), dysplastic nevus (n = 2) and juvenile melanoma (n = 3) was undetectable or detected in only a few cells. Superficial spreading melanoma (SSM) (n = 3) and acral lentiginous melanoma (ALM) (n = 3) showed a moderate expression of MT1 approximately 3-MMP. In nodular melanoma (NM) (n = 2) and metastatic melanoma (n = 3), MT1 approximately 3-MMP was more intensely expressed. Double immunofluorescence demonstrated a consistent colocalization of MT2-MMP/MMP-2 and MT3-MMP/MMP-2 in the NM and metastatic melanoma cells. The colocalization of MT2,3-MMP and MMP-2 in nodular and metastatic melanoma cells suggests that MT-MMPs and MMP-2 co-operate in the invasive and metastatic process of melanoma cells.

Humans↗
PubMed2001

Cloning and characterization of a rat ortholog of MMP-23 (matrix metalloproteinase-23), a unique type of membrane-anchored matrix metalloproteinase and conditioned switching of its expression during the ovarian follicular development.

In our attempt to study the role of matrix metalloproteinases (MMPs) in the process of mammalian ovulation, we isolated a rat ortholog of the recently reported human MMP-23 from gonadotropin-primed immature rat ovaries. Transient expression of epitope-tagged rat and human MMP-23 in COS-1 cells revealed that they were synthesized as a membrane-anchored glycoprotein with type II topology. Indirect immunofluorescent analysis showed that subcellular localization of MMP-23 was predominantly in the perinuclear regions. The transfected human MMP-23 protein was processed endogenously to the soluble form in COS-1 cells. However, cotransfection of MMP-23 with the mouse furin cDNA did not enhance this processing, indicating that furin may not be involved in this event. Notably, in situ hybridization analysis revealed a dramatic switching of MMP-23 mRNA localization from granulosa cells to theca-externa/fibroblasts and ovarian surface epithelium during the follicular development. In serum-free primary culture of rat granulosa cells, a drastic diminution of MMP-23 mRNA expression was observed in response to FSH action between 24 h and 48 h of culture. The observed effect of FSH on MMP-23 expression was mimicked by treatment of granulosa cells with forskolin or 8-bromo (Br)-cAMP. In contrast, MMP-23 mRNA levels increased in theca-interstitial cells regardless of the presence of LH in the culture. However, treatment of theca-interstitial cells with forskolin or 8-Br-cAMP markedly reduced the expression of MMP-23 with a concomitant increase in progesterone production. These results indicate that the MMP-23 gene is spatially and temporally regulated in a cell type-specific manner in ovary via the cAMP signaling pathway.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations.

BACKGROUND: Glucose intake has been shown to cause an increase in intranuclear nuclear factor-kappa B and a decrease in inhibitor kappa B that are consistent with a proinflammatory effect. We investigated the effect of glucose intake on 2 other proinflammatory transcription factors, activator protein 1 (AP-1) and early growth response 1 (Egr-1), and on the genes regulated by them, ie, the genes for matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and tissue factor (TF), respectively. OBJECTIVE: The objective of the study was to ascertain whether the intake of 75 g glucose induces an increase in AP-1, Egr-1, and the genes regulated by them. DESIGN: Eight healthy subjects were given 75 g glucose dissolved in 300 mL water to drink. Blood samples were collected before and 1, 2, and 3 h after glucose intake. Four weeks later, the same subjects were given 300 mL water sweetened with saccharine, and blood samples were collected at the same time points. Mononuclear cells (MNCs) were separated, and nuclear fractions were isolated. RESULTS: AP-1 and Egr-1 binding activities were significantly higher 1 and 2 h after glucose intake and then decreased toward the baseline by 3 h. The expression of MMP-2 and TF in MNC homogenates also was significantly higher at 2 and 3 h. Plasma concentrations of MMP-2 were significantly higher at 3 h, whereas those of MMP-9 were significantly higher at 1, 2, and 3 h. In addition, TF was significantly higher at 2 and 3 h. Intake of saccharine-sweetened water had no significant effect on the inflammatory mediators measured in this study. CONCLUSION: Glucose induces proinflammatory changes, including increases in AP-1, Egr-1, MMPs, and TF, the factors that regulate processes that are potentially relevant to atherosclerotic plaque rupture and thrombosis.

Adult↗
PubMed2004

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line.

Local invasiveness is a characteristic feature of glioblastoma that makes surgical resection nearly impossible and accounts in large part for its poor prognosis. To identify mechanisms underlying glioblastoma invasion and motility, we used Transwell invasion chambers to select for a more potently invasive subpopulation of U87MG human glioblastoma cells. The stable population of tumor cells (U87-C1) obtained through this in vitro selection process were three times more invasive than parental U87MG cells and demonstrated faster monolayer wound healing and enhanced radial motility from cell spheroids. This enhanced invasiveness was associated with an 80% increase in matrix metalloproteinase 2 (MMP-2) activation. No differences in expression levels of pro-MMP-2, membrane-type matrix metalloproteinase I (MT1-MMP), or integrin alphavbeta3 (mediators of MMP-2 activation) were detected. However, U87-C1 cells exhibited two-fold elevation of tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and protein relative to parental cells. Exogenous addition of comparable levels of purified TIMP-2 to parental U87MG cells increased MMP-2 activation and invasion. Similarly, U87MG cells engineered to overexpress TIMP-2 at the same levels as U87-C1 cells also demonstrated increased MMP-2 activation, indicating that an increase in physiological levels of TIMP-2 can promote MMP-2 activation and invasion in glioblastoma cells. However, exogenous administration or recombinant overexpression of higher amounts of TIMP-2 in U87MG cells resulted in inhibition of MMP-2 activation. These results demonstrate that the complex balance between TIMP-2 and MMP-2 is a critical determinant of glioblastoma invasion, and indicate that increasing TIMP-2 in glioblastoma patients may potentially cause adverse effects, particularly in tumors containing high levels of MT1-MMP and MMP-2.

Cell Line, Tumor↗
PubMed2001

The design, structure, and therapeutic application of matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

Amino Acid Sequence↗
PubMed2004

The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. Under normal physiological conditions, the activities of these enzymes are well-regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. Because of their importance in a variety of pathological conditions, a number of small molecular weight MMP inhibitors have entered clinical trials in humans. However, the results of these trials have been extremely disappointing and have led many investigators to conclude that MMP inhibitors have no therapeutic benefit in human cancer. To date, the first generation MMP inhibitors exhibited poor bioavailability while second-generation compounds revealed that prolonged treatment caused musculoskeletal pain and inflammation or had a lack of efficacy. This article describes the design of small molecular weight MMP inhibitors, a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMP inhibitors, and a clinical update of compounds that have entered clinical trials in humans. The experimentally determined structures used in the structure-based design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published and/or patented potent MMP inhibitors, from approximately January 2000 to April 2003, and their pharmacological properties. Protein inhibitors of these proteolytic enzymes, i.e. TIMPs, will not be discussed.

Animals↗
PubMed2000

Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation.

Matrix metalloproteinases characterized so far are either secreted or membrane anchored via a type I transmembrane domain or a glycosylphosphatidylinositol linkage. Lacking either membrane-anchoring mechanism, the newly discovered CA-MMP/MMP-23 was reported to be expressed as a cell-associated protein. In this report, we present evidence that CA-MMP is expressed as an integral membrane zymogen with an N-terminal signal anchor, and secreted as a fully processed mature enzyme. We further demonstrate that L(20)GAALSGLCLLSALALL(36) is required for this unique membrane localization as a signal anchor and its secretion is regulated by a proprotein convertase motif RRRR(79) sandwiched between its pro- and catalytic domains. Thus, CA-MMP is a type II transmembrane MMP that can be regulated by a single proteolytic cleavage for both activation and secretion, establishing a novel paradigm for protein trafficking and processing within the secretory pathway.

Amino Acid Motifs↗
PubMed2000

Expression and activation of matrix metalloproteinase-2 (MMP-2) and its co-localization with membrane-type 1 matrix metalloproteinase (MT1-MMP) correlate with melanoma progression.

Matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) play an important role in cancer cell invasion and metastasis. Recently, it was shown that the presence of activated MMP-2 correlates with melanoma progression in vitro. This activation involves coordinated expression of MMP-2, membrane-type 1 MMP (MT1-MMP), and TIMP-2. To investigate the expression profile of these enzymes in human melanoma, this study used tumour specimens obtained from both a human melanoma xenograft model, consisting of eight melanoma cell lines with different metastatic capacity in nude mice, and 60 fresh human cutaneous melanocytic lesions comprising all stages of melanocytic tumour progression. MT1-MMP and TIMP-2 mRNA and protein were present in all cell lines. Cell surface expression level of MT1-MMP, as determined by flow cytometry, was similar on all cell lines. In addition, western blot analysis revealed that both inactive and active MT1-MMP protein was expressed by all cell lines. MMP-2 mRNA and the pro-enzyme form of MMP-2 were expressed by all cell lines. Remarkably, the presence of functionally active MMP-2 was restricted to the most aggressive cell lines MV3 and BLM. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA isolated from subcutaneous xenografts revealed MT1-MMP and TIMP-2 mRNA expression in all lesions, whereas MMP-2 mRNA could be detected only in xenografts derived from the highly metastatic cell lines 1F6m, MV3, and BLM. Furthermore, immunohistochemistry demonstrated a marked increase of MMP-2 and MT1-MMP in MV3 and BLM xenografts, whereas TIMP-2 expression showed no evident correlation with metastatic capacity. In human cutaneous melanocytic lesions, MMP-2, MT1-MMP, and TIMP-2 mRNA were detectable by RT-PCR in all lesions. Expression of MMP-2 protein was not detectable, either in common and atypical naevi, or in melanoma in situ by immunohistochemistry. In these lesions, heterogeneous expression of MT1-MMP and TIMP-2 was present in melanocytic cells. In contrast, a large number of MMP-2 and MT1-MMP-positive tumour cells were observed in primary melanomas and melanoma metastases. Double staining experiments and immunohistochemistry on serial sections from the same lesions demonstrated that all tumour cells expressing MMP-2 also expressed MT1-MMP and TIMP-2. Finally, zymography of melanoma metastases revealed that MMP-2 was present in its functionally active form. This study demonstrates that expression of MT1-MMP and TIMP-2 and activation of MMP-2 are correlated with tumour progression both in the xenograft model and in human melanocytic lesions, strongly suggesting that these factors are required for melanoma invasion and metastasis formation.

Animals↗
PubMed2003

Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.

The matrix metalloproteinases (MMPs) constitute a family of multidomain zinc endopeptidases with a metzincin-like catalytic domain, which are involved in extracellular matrix degradation but also in a number of other important biological processes. Under healthy conditions, their proteolytic activity is precisely regulated by their main endogenous protein inhibitors, the tissue inhibitors of metalloproteinases. Disruption of this balance results in pathophysiological processes such as arthritis, tumor growth and metastasis, rendering the MMPs attractive targets for inhibition therapy. Knowledge of their tertiary structures is crucial for a full understanding of their functional properties and for rational drug design. Since the first appearance of atomic MMP structures in 1994, a large amount of structural information has become available on the catalytic domains of MMPs and their substrate specificity, interaction with synthetic inhibitors and the TIMPs, the domain organization, and on complex formation with other proteins. This review will outline our current structural knowledge of the MMPs and the TIMPs.

Catalytic Domain↗
PubMed2001

Matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor-2 of matrix metalloproteinases (TIMP-2) in the placenta and interplacental uterine wall in normal cows and in cattle with retention of fetal membranes.

Matrixmetalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a key role in tissue re-modelling in the placenta. In the present study, distribution of MMP-2, MMP-9 and TIMP-2 was demonstrated immunohistochemically in the bovine placenta and interplacentomal tissue. Specimens representing the whole gestation until parturition were processed. Additionally, materials from cows with and without retention of fetal membranes were compared. MMP-2 expression was abundant in the maternal septae of the placentome in early gestation, with ongoing pregnancy immunoreactivity was restricted to the stromal tissue at the openings of maternal crypts. The chorionic epithelium opposite to these regions was also positive for MMP-2. MMP-9 expression was observed in the chorionic epithelium, except in the giant binucleate cells. In addition, the maternal epithelium and stroma showed immunoreactivity for MMP-9. No differences in MMP-2 and MMP-9 distribution could be observed between cows with proper release of fetal membranes and cows with retained fetal membranes. Giant binucleate cells expressed TIMP-2 during the whole gestation. Immunostaining for alpha-smooth muscle actin revealed contractile elements in the bovine placentome. Balance between proteolytic enzymes and their activators and inhibitors is essential for regular development of the placenta. The expression of TIMP-2 in the giant binucleate cells indicates an essential role of inhibitory factors during gestation. It is likely that less TIMP-2 is produced at the end of pregnancy as the number of binucleate cells is diminished.

Actins↗