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PubMed2004

Cleavage of focal adhesion kinase in vascular smooth muscle cells overexpressing membrane-type matrix metalloproteinases.

BACKGROUND: Membrane-type matrix metalloproteinases (MT-MMPs) were initially identified as cell surface activators of MMP-2 (gelatinase A). We have reported that MT1-MMPs and MT3-MMPs are expressed by activated vascular smooth muscle cells (SMCs) and play a role in the regulation of cell function. Overexpression of MT-MMPs results in cell rounding, decreased adherence, and increased migration. Because integrin-mediated cell adhesion regulates these events, we have investigated the functional relationship between MT-MMPs and focal adhesion assembly. METHODS AND RESULTS: Using adenoviral vectors we show that overexpression of MT-MMPs reduces the number of focal contacts, whereas the cell surface expression of integrin subunits remains unchanged. The 125-kDa focal adhesion kinase (FAK) is cleaved resulting in a 90-kDa fragment under these conditions, and paxillin is partially dissociated from FAK after its cleavage. Pretreatment of cells with BB94, a synthetic MMP inhibitor, rescues cell adhesion and prevents changes in focal adhesions, supporting a potential role for MT-MMP enzymatic activities. CONCLUSIONS: This study provides the first evidence that MT-MMPs are not only important in matrix degradation but also may affect the function of focal adhesions through FAK cleavage.

Actin Cytoskeleton↗
PubMed2004

Matrix metalloproteinase genes in Xenopus development.

Matrix metalloproteinases (MMPs) are a large family of proteins in vertebrates, consisting of over 24 genes in humans, only a few of which have been identified in Xenopus. Three genes coding for MMPs in Xenopus have been identified and their expression studied during development. The membrane-bound XMMP-14 and -15 (XMT1-MMP and XMT2-MMP) both showed restricted expression patterns, the former principally localising to cranial neural crest tissues and the latter to the epidermis of the embryo. XMMP-7 codes for an MMP that lacks the hemopexin-like domain. It is expressed exclusively in macrophages or other myeloid cell types from early in development.

Amino Acid Sequence↗
PubMed1999

Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases.

The tissue inhibitors of matrix metalloproteinases (MMPs), TIMP-1 and TIMP-2, are also angiogenesis inhibitors. Cathepsin B and MMPs are found at sites of neovascularization in pathologies such as cancer and osteoarthritis. Treatment of TIMP-1, TIMP-2, and of a mixture of both inhibitors from human articular chondrocytes with cathepsin B resulted in their fragmentation, whereby they lost their MMP-inhibitory and anti-angiogenic activities. Our data suggest that, besides directly participating in tissue destruction, cathepsin B can be harmful for two further reasons: it raises the activity of the MMPs also in the absence of mechanisms up-regulating these enzymes, and it stimulates angiogenesis. This is a prerequisite for blood vessel invasion in a variety of pathological situations of which cancer and osteoarthritis are prominent examples.

Cartilage, Articular↗
PubMed2000

Induction of matrix metalloproteinases 2 and 9 following stress to the lens.

Matrix metalloproteinase 2 and 9 (MMP-2 and 9, also known as gelatinase A and B) have been implicated in a number of eye diseases, but their possible involvement in lens pathology is yet to be determined. In the present study, we therefore investigated a possible role of matrix metalloproteinases in cataract and posterior capsule opacification. Whole porcine lenses were removed from the eye and cultured in either Eagles Minimum Essential Medium (EMEM) or EMEM supplemented with 1 m M hydrogen peroxide. The medium was sampled and changed every 2 days. On some occasions a sham cataract operation was performed on cultured lenses. The resulting capsular bag was secured to a Petri dish and cultured in EMEM. Culture media from all preparations were analysed for MMP-2 and 9 activity by gelatin zymography. Media samples from lenses which maintained clarity over the 6 day culture period did not display any detectable gelatinolytic activity. However, media from cataractous lenses demonstrated a gelatinolytic band, which had similar molecular weights to the pro-form of MMP-2. In addition to this band, bands with a similar molecular weight to pro-MMP-9 and its dimeric form were also detected in samples obtained from capsular bag preparations within 24 hr. The data presented indicate that normal lenses have undetectable gelatinase activity. However, there is an associated expression of gelatinases with pathological states of the lens, and therefore gelatinase expression could play an important role in cataractogenesis and posterior capsule opacification.

Animals↗
PubMed2006

Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes.

Matrix metalloproteinase-9 (MMP-9) may play a role in the inflammatory glial response during Alzheimer's disease (AD). Astrocytes can degrade beta-amyloid (Abeta) and extracellular proteolysis via MMP-9 may be involved. Because Apolipoprotein E (APOE) genotype is an important factor for AD, we ask whether various apoE isoforms can influence Abeta-induced MMP-9 responses in primary rat astrocytes. Our data show that apoE4 significantly dampens Abeta-induced MMP-9 levels, possibly by downregulating the Rho-Rho kinase (ROCK) pathway. Reduction of astrocytic MMP-9 by apoE4 may affect Abeta clearance and promote Abeta deposition in AD.

Alzheimer Disease↗
PubMed2001

Invasiveness of cutaneous malignant melanoma is influenced by matrix metalloproteinase 1 gene polymorphism.

The matrix metalloproteinases (MMPs) are implicated in connective tissue destruction during cancer invasion and metastasis. A naturally occurring variant arising from the insertion or deletion of a guanine in the promoter of the MMP-1 gene has recently been reported and shown to influence its transcriptional activity in melanoma cells. In this study, MMP-1 genotype was determined in 139 Caucasian patients with cutaneous malignant melanoma. The insertion allele was associated with deep invasive, and therefore poorer-prognosis, primary tumors [(34% of patients with vertical growth phase tumor were homozygous for the insertion allele compared with 17% of patients with horizontal growth phase tumor (P = 0.0333; odds ratio = 2.51)]. These data suggest that the invasiveness of cutaneous malignant melanoma is influenced by variation in the MMP-1 gene promoter that affects MMP-1 expression.

Cell Division↗
PubMed2004

The evolution of the matrix metalloproteinase inhibitor drug discovery program at abbott laboratories.

Matrix metalloproteinases (MMPs) have been implicated in several pathologies. At Abbott Laboratories, the matrix metalloproteinases inhibitor drug discovery program has focused on the discovery of a potent, selective, orally bioavailable MMP inhibitor for the treatment of cancer. The program evolved from early succinate-based inhibitors to utilizing in-house technology such as SAR by NMR to develop a novel class of biaryl hydroxamate MMP inhibitors. The metabolic instability of the biaryl hydroxamates led to the discovery of a new class of N-formylhydroxylamine (retrohydroxamate) biaryl ethers, exemplified by ABT-770 (16). Toxicity issues with this pre-clinical candidate led to the discovery of another novel class of retrohydroxamate MMP inhibitors, the phenoxyphenyl sulfones such as ABT-518 (19j). ABT-518 is a potent, orally bioavailable, selective inhibitor of MMP-2 and 9 over MMP-1 that has been evaluated in Phase I clinical trials in cancer patients.

Animals↗
PubMed2003

Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase.

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is known to be internalized from cell surface, however, the fate of internalized MT1-MMP is still unknown. Here we demonstrate that at least a part of internalized MT1-MMP is targeted for lysosomal proteolysis. Treatment with an inhibitor of lysosomal proteinases chloroquine suppressed degradation of internalized MT1-MMP and induced accumulation of MT1-MMP in CD63-positive lysosomes. Ectopic expression of CD63 accelerated degradation of MT1-MMP, which was blocked by chloroquine. MT1-MMP, and CD63 were shown to form a complex through hemopexin-like domain of MT1-MMP and N-terminal region of CD63, and thus accelerated degradation of MT1-MMP was not observed with mutants lacking these domains. CD63 mutant lacking lysosomal targeting motif was unable to promote MT1-MMP degradation. These results suggest that CD63 regulates MT1-MMP by targeting to lysosomes.

Animals↗
PubMed2006

The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors.

At least 56 matrix metalloproteinase (MMP) inhibitors have been pursued as clinical candidates since the late 1970's when the first drug discovery program targeting this enzyme family began. Some of these clinical candidates were pursued for multiple indications. However, the two primary indications that have been targeted are cancer (24 drugs) and anti-arthritis (27 drugs). Cardiovascular disease was listed as an indication for 10 drugs. Forty-six MMP inhibitors have been discontinued, 7 remain in clinical development, and only 1 (Periostat for periodontal disease) has been approved. Recently, negative phase II results were reported for the MMP inhibitor PG-116800, which was being evaluated as a treatment for post-ischemic myocardial remodeling to prevent heart failure. One major factor leading to the failure of PG-116800 and many of the other MMP inhibitors is the inadequate assessment of the therapeutic index, the ratio of dose required for efficacy vs. that for toxicology. This review describes the dose-limiting side effect that has hampered MMP inhibitor development (the musculoskeletal syndrome), cardiovascular clinical MMP inhibitor studies, a model of the therapeutic index using marimastat, and progress towards more selective MMP inhibitors not limited by the musculoskeletal syndrome.

Cardiovascular Diseases↗
PubMed2001

Blood specimen collection methods influence the concentration and the diagnostic validity of matrix metalloproteinase 9 in blood.

BACKGROUND: Matrix metalloproteinases (MMP) in blood are promising new diagnostic tools. It was shown that the blood sampling process resulted in different blood concentrations of MMPs. To clarify whether the sampling process also influences the diagnostic validity of MMPs, MMP-9 measurements were performed in plasma and serum samples of patients with prostate carcinoma and renal cell cancer. METHODS: MMP-9 ELISAs were performed in samples of heparin plasma and serum collected in blood tubes with and without clot accelerator. Measurements were undertaken in 78 healthy persons, 33 patients with prostate carcinoma and 33 patients with renal cell carcinoma. RESULTS: MMP-9 showed higher concentrations in serum samples than in heparin plasma and was about threefold higher in serum samples collected in tubes with clot activator than in native serum samples. Both patient groups had lower MMP-9 concentrations in serum, whereas in plasma, patients with renal cell carcinoma had higher, but patients with prostate cancer unchanged MMP-9 concentrations. 13 of 33 patients with renal cell carcinoma had increased MMP-9 plasma values but no patient had increased serum concentrations. CONCLUSIONS: To optimise the diagnostic validity of the MMP-9 in blood, measurements should be performed in heparin plasma but not in serum.

Blood Specimen Collection↗
PubMed2005

CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase.

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a potent modulator of pericellular environment through its proteolytic activity and promotes migration, invasion, and proliferation of tumor cells. During cell migration, MT1-MMP binds to CD44H, a major hyaluronan receptor, through the hemopexin-like (HPX) domain and localizes at the migration front. MT1-MMP is also responsible for shedding CD44H, which supports CD44H-mediated cell migration. In this study, we asked whether the binding of MT1-MMP to CD44H is a prerequisite step for the successive shedding. Deletion of the HPX domain deprived MT1-MMP of its shedding activity. Furthermore, disruption of the CD44H/MT1-MMP complex by overexpressing the HPX fragments resulted in inhibition of the shedding. Thus, the CD44H in the complex appears to be the direct substrate of MT1-MMP for shedding. Interestingly, other members of the MT-MMP family showed varied extents of CD44H shedding. Domain swapping between MT1-MMP and other MT-MMPs revealed that the ability of the HPX domains to bind CD44H is conserved among them. However, the shedding activity was different depending on the catalytic domains. The conserved binding ability of the HPX domains suggests that CD44H may act as a core molecule assembling multiple MT-MMPs on the cell surface.

Binding Sites↗
PubMed2006

Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice.

Among matrix metalloproteinases (MMP), MMP-19 displays unique structural features and tissue distribution. In contrast to most MMPs, MMP-19 is expressed in normal human epidermis and down-regulated during malignant transformation and dedifferentiation. The contribution of MMP-19 during tumor angiogenesis is presently unknown. In an attempt to give new insights into MMP-19 in vivo functions, angiogenic response of mutant mice lacking MMP-19 was analyzed after transplantation of murine malignant PDVA keratinocytes and after injection of Matrigel supplemented with basic fibroblast growth factor. In situ hybridization and immunohistochemical analysis revealed that MMP-19 is produced by host mesenchymal cells but not by endothelial capillary cells or CD11b-positive inflammatory cells. Based on a new computer-assisted method of quantification, we provide evidence that host MMP-19 deficiency was associated with an increased early angiogenic response. In addition, increased tumor invasion was observed in MMP-19-/- mice. We conclude that, in contrast to most MMPs that promote tumor progression, MMP-19 is a negative regulator of early steps of tumor angiogenesis and invasion. These data highlight the requirement to understand the individual functions of each MMP to improve anticancer strategies.

Animals↗
PubMed1995

The C-terminal region of membrane type matrix metalloproteinase is a functional transmembrane domain required for pro-gelatinase A activation.

We identified a new matrix metalloproteinase (membrane type matrix metalloproteinase (MT-MMP)) that has a potential transmembrane (TM) domain at the C terminus and reported its expression on the surface of invasive tumor cells. The expression of MT-MMP induced specific activation of 72-kDa pro-gelatinase A (Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) Nature 370, 61-65). Thus, MT-MMP on the cell surface is thought to play an important role in various physiological and pathological processes accompanying tissue remodeling. In this study, we demonstrated that the potential TM domain deduced from the amino acid sequence functions as a membrane linker when it is fused to a secretory protein, tissue inhibitor of matrix metalloproteinases-1. The pro-gelatinase A activation function of MT-MMP was abolished by truncation of the TM domain and recovered by fusing the MT-MMP mutant with the TM domain of interleukin 2 receptor alpha-chain. The truncated MT-MMP was released from the cells into the medium and detected as processed or modified forms. In spite of the deletion of the TM domain some portions of the mutant MT-MMP were still retained on the surface of cells. Thus, MT-MMP has an additional device to keep it on the cell surface. The TM domain however, plays an essential role in the pro-gelatinase A activation function of MT-MMP, probably regulating its fine orientation or the localization that is necessary to interact with substrate.

Animals↗
PubMed1995

Unique regulation of the matrix metalloproteinase, gelatinase B.

PURPOSE: The matrix metalloproteinase (MMP), gelatinase B, is expressed by both corneal cell types found at the epithelial-stromal tissue interface, the site of basement membrane repair in the healing cornea. This study investigates the relative regulation of gelatinase B compared to other MMPs in response to agents related to those found in the corneal repair environment or in corneal ulcers. METHODS: A culture model of corneal cells isolated from rabbit was used. RESULTS: Gelatinase B is the major MMP expressed by corneal epithelial cells, whereas stromal fibroblasts produce gelatinase B along with three other MMPs: collagenase, stromelysin, and gelatinase A. Phorbol-12-myristate 13-acetate (PMA) stimulates gelatinase B mRNA and protein synthesis by corneal cells, which is similar to its effect on the other MMPs. Stimulation occurs, at least partially, at the transcriptional level. PMA-stimulated MMP expression follows biphasic kinetics, with the major effect on collagenase, stromelysin, and gelatinase A occurring during the late component. In contrast, the major gelatinase B response occurs during the early component. Transforming growth factor-beta (TGF-beta) has no effect on constitutive expression of gelatinase B by fibroblasts; however, expression stimulated by PMA is enhanced. In contrast, constitutive expression of collagenase and stromelysin is inhibited by TGF-beta. However, in the presence of PMA, the initial inhibitory effect of TGF-beta is reversed after treatment. CONCLUSION: Gelatinase B expression is regulated differently from other corneal MMPs. This provides a mechanism for control of basement membrane repair independent of repair processes in the stroma.

Animals↗
PubMed1994

Design and characterization of a fluorogenic substrate selectively hydrolyzed by stromelysin 1 (matrix metalloproteinase-3).

Members of the matrix metalloproteinase (MMP) family have been implicated in disease states such as arthritis, periodontal disease, and tumor cell invasion and metastasis. Stromelysin 1 (MMP-3) has a broad substrate specificity and participates in the activation of several MMP zymogens. We examined known sequences of MMP-3 cleavage sites in natural peptides and proteins and compared sequence specificities of MMP-3 and interstitial collagenase (MMP-1) in order to design fluorogenic substrates that (i) would be hydrolyzed rapidly by MMP-3, (ii) would discriminate between MMP-3 and MMP-1, and (iii) could be monitored continuously without interference from MMP amino acid residues. Designed substrates were then screened for activity toward MMP-1, gelatinase A (MMP-2), MMP-3, and gelatinase B (MMP-9). The first of these substrates, NFF-1 (Mca-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Lys-(Dnp)-Gly, where Mca is (7-methoxycoumarin-4-yl)acetyl and Dnp is 2,4-dinitrophenyl), was hydrolyzed equally well by MMP-3 and MMP-2 (kcat/Km approximately 11,000 s-1 M-1). MMP-1 had 25% of the activity of MMP-3 toward NFF-1. The second substrate, NFF-2 (Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH2, where Nva is norvaline), was hydrolyzed 60 times more rapidly by MMP-3 (kcat/Km = 59,400 s-1 M-1) than MMP-1. Unfortunately, NFF-2 showed little discrimination between MMP-3, MMP-2 (kcat/Km = 54,000 s-1 M-1), and MMP-9 (kcat/Km = 55,300 s-1 M-1). The third substrate, NFF-3 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2), was hydrolyzed rapidly by MMP-3 (kcat/Km = 218,000 s-1 M-1) and very slowly by MMP-9 (kcat/Km = 10,100 s-1 M-1), but there was no significant hydrolysis by MMP-1 and MMP-2. NFF-3 is the first documented synthetic substrate hydrolyzed by only certain members of the MMP family and thus has important application for the discrimination of MMP-3 activity from that of other MMPs. Although NFF-3 was designed by assuming that substrate subsites were independent and hence free energy changes derived from single mutation experiments were additive, we found discrepancies between predicted and experimental kcat/Km values, one on the order of 2000-5000. Thus, the design of additional discriminatory MMP substrates may require approaches other than assuming additive free energy changes, such as screening synthetic libraries and consideration of secondary and tertiary structures of substrates and the enzyme.

Amino Acid Sequence↗
PubMed1998

Oligodendrocytes utilize a matrix metalloproteinase, MMP-9, to extend processes along an astrocyte extracellular matrix.

Matrix metalloproteinases (MMPs), the key effectors of extracellular matrix remodeling, have been demonstrated to regulate the extension of neurites from neuronal cell bodies. In this report we have addressed the hypothesis that oligodendrocytes (OLs) may utilize a similar mechanism in extending their processes during the initial phase of myelination. Furthermore, given our previous findings linking protein kinase C (PKC) to the OL process outgrowth, we tested the postulate that this signal transduction pathway may regulate MMPs and thus the process outgrowth phenotype. We demonstrate that in response to pharmacologic activators of PKC, cultured human OLs augment their process extension with a concomitant increase in the activity of an MMP, MMP-9, as measured by gelatin zymography. Similarly, the phorbol ester-enhanced process extension and increased MMP-9 activity were both inhibited by calphostin C, a selective PKC inhibitor. Also, MMP inhibitors such as 1,10-phenanthroline and synthetic dipeptides that inactivate the MMP catalytic site negated the 4beta-phorbol-12,13-dibutyrate (PDB)-mediated process extension, further supporting the key role of MMPs in process extension in vitro. Finally, the elevation of MMP-9 protein expression in the mouse corpus callosum, a tissue rich in OL and myelin, coincided with the previously documented temporal increase in myelination that occurs postnatally. Taken together, these data suggest that MMP-9 constitutes an important mediator of OL process outgrowth, and that this protease in turn can be regulated by PKC. The results are relevant not only to the initial steps of myelination during development, but also to the attempted remyelination that has been shown to occur in pathologic conditions such as MS.

Animals↗
PubMed2000

Matrix metalloproteinase-9 and tensile strength of fetal membranes in uncomplicated labor.

OBJECTIVE: To analyze the relation between tensile strength and levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 at a number of sites in human fetal membranes. METHODS: Tensile strengths of fetal membranes from five women who delivered vaginally at term were measured by the method of modified force application. A piece of membrane at each measured site was then dissected, and the levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 were measured by sandwich enzyme immunoassay. The relationship between tensile strength and enzyme levels was evaluated by Scheffé F test at a total of 81 sites on the five membranes. RESULTS: The mean tensile strength of the membranes was 45.3 +/- 19.8 (mean +/- standard deviation) mmHg/0.3 mm(2) (n = 81). When the measured sites were divided according to tensile strength into four groups (<25, 25-49, 50-74, and >/=75 mmHg/0.3 mm(2)), the level of matrix metalloproteinase-9 (0.72 +/- 0.82 nmol/g protein, n = 12) in the less than 25 mmHg/0.3 mm(2) group was significantly higher than the other groups (0.35 +/- 0.22, 0.28 +/- 0.15, and 0.15 +/- 0.08 nmol/g protein; n = 39, 23, and 7, respectively). The significance level was still higher when the molar ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 was used for comparison. CONCLUSION: An increased molar ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 might be related to decreased tensile strength of human fetal membranes in uncomplicated labor.

Extraembryonic Membranes↗
PubMed1998

Induction of matrix metalloproteinase-9 requires a polymerized actin cytoskeleton in human malignant glioma cells.

Alterations in cytoskeleton and subsequent cell shape changes exert specific effects on the expression of various genes. Our previous results suggested that malignant human gliomas express elevated levels of matrix metalloproteinases compared with normal brain tissue and low grade gliomas. To understand the role of cell shape changes on matrix metalloproteinase expression in human glioma cells, we treated SNB19 cells with cytochalasin-D, an inhibitor of actin polymerization, and colchicine-B, a tubulin inhibitor, in the presence of phorbol 12-myristate 13-acetate. Cytochalasin-D treatment of SNB19 cells resulted in the loss of phorbol 12-myristate 13-acetate-induced matrix metalloproteinase-9 (also known as gelatinase-B) expression and coincided with inhibition of actin polymerization, resulting in cell rounding. Moreover, compared with monolayers, cells grown as spheroids or cell aggregates failed to express matrix metalloproteinase-9 in the presence of phorbol 12-myristate 13-acetate. Matrix metalloproteinase-9 expression was also inhibited by calphostin-C, a protein kinase inhibitor, suggesting the involvement of protein kinase C in matrix metalloproteinase-9 expression. Phorbol 12-myristate 13-acetate-induced invasion of SNB19 cells through Matrigel was inhibited by cytochalasin-D and calphostin-C. These results suggest that the actin polymerization transduces signals that modulate the expression of matrix metalloproteinase-9 expression and the subsequent invasion of human glioma cells.

Actins↗