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PubMed2006

Response of matrix metalloproteinase-9 to olfactory nerve injury.

Matrix metalloproteinases function in the remodeling of the extracellular matrix during growth and development as well as in injury and disease processes. We examined the role of matrix metalloproteinase-9 in a model of olfactory nerve injury in mice. We measured changes in matrix metalloproteinase-9 protein levels for up to 60 days following olfactory nerve transection. Matrix metalloproteinase-9 levels increased within hours after injury, peaked at day 1 and were elevated for approximately 2 weeks before returning to control levels over the 60-day time period. The increase in matrix metalloproteinase-9 was temporally associated with the degeneration of olfactory neurons that follows nerve transection and with increased gliosis. Our results demonstrate a temporal relationship between matrix metalloproteinase-9 elevation, degeneration of olfactory neurons and gliosis.

Animals↗
PubMed2003

Regulation of matrix metalloproteinases: an overview.

Matrix metalloproteinases (MMPs) are a major group of enzymes that regulate cell-matrix composition. MMP genes show a highly conserved modular structure. Ample evidence exists on the role of MMPs in normal and pathological processes, including embryogenesis, wound healing, inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. The expression patterns of MMPs have interesting implications for the use of MMP inhibitors as therapeutic agents. Insights might be gained as to the preference for a general MMP inhibitor as opposed to an inhibitor designed to be specific for certain MMP family members as it relates to a defined disease state, and may give clues to potential side effects. The signalling pathways that lead to induction of expression of MMPs are still incompletely understood, but certain patterns are beginning to emerge. Regarding inhibition of MMP expression at the level of kinase pathways, it is possible that selective chemical inhibitors for distinct signalling pathways (e.g. MAPK, PKC) will hopefully, soon be available for initial clinical trials. Overexpression of selective dual specificity MAPK phosphatases have been shown to prevent MMP promoter activation which could also be used as a novel strategy to prevent activation of AP-1 and ETS transcription factors and MMP promoters in vivo. Interactions between members of different transcription factors provide fine-tuning of the transcriptional regulation of MMP promoter activity. MMPs play a crucial role in tumor invasion. Although the expression of MMPs in malignancies has been studied widely, the specific role of distinct MMPs in the progression of cancer may be more complex than has been assumed. For example, it has recently been shown that MMP-3, MMP-7, MMP-9 and MMP-12 can generate angiostatin from plasminogen, indicating that their expression in peritumoral area may in fact serve to limit angiogenesis and thereby inhibit tumor growth and invasion. The recent view about the role of stromal cells in the progression of cancer cell growth and metastasis is particularly interesting, and additional studies about the regulation of MMP gene expression and activity in malignancies are needed to understand the role and regulation of MMPs in tumor cell invasion.

Animals↗
PubMed1999

Effect of microbial siderophores on matrix metalloproteinase-2 activity.

Matrix metalloproteinases (MMPs) are capable of cleaving almost all macromolecules of the extracellular connective tissue matrix and are thought to play a major role in tissue destructive inflammatory diseases such as periodontitis. The aim of this study was to determine the effects of siderophores, which are iron-chelating molecules produced by a variety of microorganisms, on the activity of MMP-2. Heat-denatured type I collagen (gelatin) was incubated with p-aminophenylmercuric acetate-activated MMP-2 and siderophores. Degradation of gelatin was monitored by SDS-PAGE and Coomassie blue staining. Ferrichrome, rhodotorulic acid, desferoxamine mesylate and 2,3-dihydroxybenzoic acid were found to inhibit the MMP-2 activity whereas beta-phenylpyruvic acid had no effect. The inhibition could be reversed by adding an excess calcium chloride or ferric chloride to the assay mixtures. Our study suggests that microbial siderophores may represent new-potential therapeutic molecules for the treatment of destructive inflammatory diseases involving excess MMP-2 activity, such as periodontitis.

Bacteria↗
PubMed1997

Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases.

Membrane-type-1 matrix metalloproteinase has been identified as an activator of the matrix metalloproteinase progelatinase A at cell surfaces. We report here that a soluble active form of membrane-type-2 matrix metalloproteinase can also process progelatinase A in a comparable fashion to the type-1 at rates which are dependent on the concentration of the proenzyme. Activation is inhibited by tissue inhibitors of metalloproteinases TIMP-2 and TIMP-3, but only partially by TIMP-1. These results suggest that cellular activation of progelatinase A may be initiated by different members of the membrane-type matrix metalloproteinase family depending on tissue distribution.

Amino Acid Sequence↗
PubMed1998

Expression and localization of membrane type 1 matrix metalloproteinase in tooth tissues.

Matrix metalloproteinases (MMPs) have been detected in forming dental enamel and are thought to play an important role during enamel biomineralization. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane bound member of the MMP gene family that has previously been shown to be expressed by cells associated with bone and cartilage formation (osteoclasts, osteoblasts and chondrocytes). Thus, we asked if MT1-MMP was also expressed by the cells responsible for the formation of enamel and dentin. A porcine MT1-MMP cDNA composed of 3284 bp was isolated from an enamel organ-specific cDNA library. Multiple tissue Northern blot analysis revealed that the MT1-MMP message was expressed highly in the enamel organ and pulp organ when compared to the expression levels observed in other non-mineralizing tissues. Northern blot analysis of stage-specific enamel organs (early secretory, late secretory, or maturation stage) and their corresponding pulp organs revealed that MT1-MMP expression increased as the dentin matured. In the enamel organs, however, the MT1-MMP message level became reduced only during the late secretory stage. Immunohistochemical analysis showed that MT1-MMP was present on the surface of the cells (ameloblasts and odontoblasts) responsible for dentin and enamel formation. Thus, MT1-MMP is highly expressed in developing tooth tissues and may play a role in the biomineralization of enamel and dentin.

Ameloblasts↗
PubMed2001

Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions.

Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) is a heavily glycosylated protein containing two immunoglobulin superfamily domains. It is enriched on the surface of tumor cells and stimulates the production of matrix metalloproteinases (MMPs) by adjacent stromal cells. Here we use CD147 transfectants and immobilized recombinant CD147-Fc fusion protein to show that CD147/FMMPRIN engages in a homophilic interaction, predominantly through the first immunoglobulin domain. Anti-CD147 antibody 8G6 and recombinant CD147-Fc fusion protein markedly inhibited not only homophilic interaction, but also the production of secreted MMP-2 by breast cancer cell line MDA-435 and the MMP-2-dependent invasion of MDA-435 cells through reconstituted basement-membrane Matrigel. Purified native CD147 induced the production of secreted MMP not only by dermal fibroblasts (MMP-1) but also by MDA-435 cells themselves (MMP-2), suggesting homophilic CD147-binding may occur in the context of both heterotypic and homotypic cell-cell interactions. Purified deglycosylated CD147 failed to induce MMP-1 or MMP-2, but instead antagonized the MMP-1-inducing activity of purified native CD147. Our results suggest that homophilic CD147 interactions may play a key role in MMP-2 production and tumor cell invasion, and that perturbation of this molecule may have potential therapeutic uses in the prevention of MMP-2 and MMP-1-dependent cancer metastasis.

Animals↗
PubMed2005

Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2.

BACKGROUND: Matrix metalloproteinase-2 (MMP-2) contributes to cardiac dysfunction resulting from ischemia-reperfusion (I/R) injury. MMP-2 not only remodels the extracellular matrix but also acts intracellularly in I/R by degrading troponin I. Whether other intracellular targets exist for MMP-2 during I/R is unknown. METHODS AND RESULTS: Isolated rat hearts were subjected to 20 minutes of ischemia and 30 minutes of reperfusion. The impaired recovery of mechanical function of the heart was attenuated by the MMP inhibitors o-phenanthroline or doxycycline. Quantitative 2D electrophoresis of homogenates of aerobically perfused hearts (control) or those subjected to I/R injury (in the presence or absence of MMP inhibitors) showed 3 low-molecular-weight proteins with levels that were significantly increased upon I/R injury and normalized to control levels by MMP inhibitors. Mass spectrometry analysis identified all 3 proteins as fragments of myosin light chain 1, which possesses theoretical cleavage recognition sequences for MMP-2 and is rapidly degraded by it in vitro. The association of MMP-2 with the thick myofilament in fractions prepared from I/R hearts was observed with immunogold electron microscopy, gelatin zymography for MMP-2 activity, and immunoprecipitation. MMP-2 was found to cleave myosin light chain 1 between tyrosine 189 and glutamine 190 at the C terminus. CONCLUSIONS: Our results demonstrate that myosin light chain 1 is another novel substrate for MMP-2 in the cardiomyocyte and that its degradation may contribute to contractile dysfunction resulting from I/R injury to the heart.

Amino Acid Sequence↗
PubMed2003

Glycosylation broadens the substrate profile of membrane type 1 matrix metalloproteinase.

Membrane type 1 matrix metalloproteinase (MT1-MMP) is a collagenolytic enzyme that has been implicated in normal development and in pathological processes such as cancer metastasis. The activity of MT1-MMP is regulated extensively at the post-translational level, and the current data support the hypothesis that MT1-MMP activity is modulated by glycosylation. Enzymatic deglycosylation, site-directed mutagenesis, and lectin precipitation assays were used to demonstrate that MT1-MMP contains O-linked complex carbohydrates on the Thr(291), Thr(299), Thr(300), and/or Ser(301) residues in the proline-rich linker region. MT1-MMP glycoforms were detected in human cancer cell lines, suggesting that MT1-MMP activity may be regulated by differential glycosylation in vivo. Although the autolytic processing and interstitial collagenase activity of MT1-MMP were not impaired in glycosylation-deficient mutants, cell surface MT1-MMP-catalyzed activation of pro-matrix metalloproteinase-2 (proMMP-2) required proper glycosylation of MT1-MMP. The inability of carbohydrate-free MT1-MMP to activate proMMP-2 was not a result of defective MT1-MMP zymogen activation, aberrant protein stability, or inability of the mature enzyme to oligomerize. Rather, our data support a mechanism whereby glycosylation affects the recruitment of tissue inhibitor of metalloproteinases-2 (TIMP-2) to the cell surface, resulting in defective formation of the MT1-MMP/TIMP-2/proMMP-2 trimeric activation complex. These data provide evidence for an additional mechanism for post-translational control of MT1-MMP activity and suggest that glycosylation of MT1-MMP may regulate its substrate targeting.

Amino Acid Sequence↗
PubMed1999

Expression of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 in acute liver injury.

BACKGROUND/AIMS: Matrix metalloproteinase-13, one of the principal neutral proteinases capable of cleaving native fibrillar collagens, is important in the degradation and remodeling of extracellular matrix. However, its precise expression in liver injury has not been characterized. We examined the kinetics of the expression of matrix metalloproteinase-13 and one of its specific inhibitors, tissue inhibitor of metalloproteinase-1, in acute liver injury in rats. METHODS: Acute liver injury was induced by administration of carbon tetrachloride or two different doses of D-galactosamine hydrochloride in Wistar rats. Hepatic matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 mRNA levels were then examined by Northern blotting. RESULTS: All rats survived after liver injury induced by carbon tetrachloride or low doses of D-galactosamine hydrochloride. However, rats died 5 days after induction of liver injury by high doses of D-galactosamine hydrochloride. In carbon tetrachloride-induced liver injury, matrix metalloproteinase-13 mRNA was transiently increased between 6 h and 1 day after injury. Tissue inhibitor of metalloproteinase-1 mRNA expression was increased between 6 h and 3 days after the peak of matrix metalloproteinase-13 expression. Similar patterns of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 expression were observed in low-dose D-galactosamine hydrochloride-induced liver injury. In contrast, in high-dose D-galactosamine hydrochloride-induced liver injury, tissue inhibitor of metalloproteinase-1 expression peaked before matrix metalloproteinase-13 expression, which was increased 2 days after injury. Both mRNA levels continued to increase until death. CONCLUSIONS: Transient expression of matrix metalloproteinase-13, followed by that of tissue inhibitor of metalloproteinase-1, was observed during recovery from acute liver injury induced by carbon tetrachloride and low-dose D-galactosamine hydrochloride. In contrast, disordered expression of matrix metalloproteinase-13 was observed in fatal liver injury caused by high-dose D-galactosamine hydrochloride. These results indicate that matrix metalloproteinase13 plays an important role in the early phase of recovery from liver injury.

Animals↗
PubMed2006

Sendai virus infection up-regulates trypsin I and matrix metalloproteinase-9, triggering viral multiplication and matrix degradation in rat lungs and lung L2 cells.

To elucidate the virus-host cell interaction, we analyzed quantitatively the expression of various cellular proteases and tumor necrosis factor-alpha (TNF-alpha) after Sendai virus infection in rat lungs and lung L2 cells. After infection, TNF-alpha mRNA levels increased rapidly to a peak on day one, and then trypsin I and matrix metalloproteinase (MMP)-9, but not MMP-2, were significantly up-regulated with a peak on day 2 in vivo. These up-regulations were confirmed in L2 cells. Up-regulation of proMMP-9 and its active convertase trypsin I seems to synergistically enhance virus multiplication and the destruction of lung matrix, resulting in the progression of pneumonia.

Animals↗
PubMed2003

Association of metalloproteinases, tissue inhibitors of matrix metalloproteinases, and proteoglycans with development, aging, and osteoarthritis processes in mouse temporomandibular joint.

The temporomandibular joint (TMJ) is an important growth and articulation center in the craniofacial complex. In aging it develops spontaneous degenerative osteoarthritic (OA) lesions. Metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS) play key roles in extracellular matrix remodeling and degradation. Gelatinase activities and immunohistochemical localization of MMP-2, -3, -8, -9, and -13 and TIMP-1 and -2 were examined in mandibular condyle cartilage of neonatal mice up to 18 months old. The most intense immunostaining for all enzymes and TIMPs and the peak of gelatinase activities were found in animals in the stages of early growth (1 week to 3 months) followed by a decrease during maturation and aging. However, clusters of positively immunoreactive chondrocytes were detected in cartilages of old animals displaying OA lesions. Positive safranin-O staining, indicative of sulfated proteoglycans (PGs), was prominent in the TMJ of newborn mice up to 3 months old followed by reduction during maturation and aging, except in regions displaying OA lesions. Temporal codistribution of PGs, MMPs, and TIMPs during skeletal maturation reflected an active growth phase, whereas their reduction coincided with the more quiescent articulating and maintenance phase in the joint cartilage. Osteoarthritic lesions were associated with both increased PG synthesis and MMP immunoreactivity, indicating limited repair activity during initial stages of osteoarthritis.

Aging↗
PubMed1998

Matrix metalloproteinases and metalloproteinase inhibitors in human interphotoreceptor matrix and vitreous.

PURPOSE: We wished to establish which matrix metalloproteinases (MMPs) and metalloproteinase inhibitors (TIMPs) were present in human interphotoreceptor matrix (IPM) and vitreous. METHODS: IPM and vitreous were obtained from postmortem human eyebank eyes. Western immunoblots were probed with antibodies against human MMPs and TIMPs. Assays specific for elastase activity were also performed. RESULTS: Immunoblot analysis indicated the presence of MMP-1 (interstitial collagenase), MMP-2 and MMP-9 (gelatinases A and B), MMP-3 (stromelysin-1) and TIMP-1, -2 and -3 in both IPM and vitreous. MMP-7 (matrilysin) and MMP-12 (metalloelastase) were not found in either IPM or vitreous. CONCLUSIONS: This is the first demonstration of the MMPs and TIMPs in human IPM and of the TIMPs in human vitreous. While these enzymes are most likely involved in normal turnover within the extracellular matrices that surround the neural retina, they may also play a role in a number of retinal diseases, particularly proliferative diabetic retinopathy and age-related macular degeneration.

Aged↗
PubMedDate not supplied

Synthesis and characterization of 111In-DTPA-N-TIMP-2: a radiopharmaceutical for imaging matrix metalloproteinase expression.

The matrix metalloproteinases (MMPs) are enzymes involved in the turnover of the extracellular matrix. Their overexpression in tumors is implicated in the metastatic process and may provide a target for diagnostic tumor imaging by using a radiolabeled inhibitor. MMPs are inhibited by endogenous tissue inhibitors of metalloproteinases (TIMPs). Thus, TIMPs are potential targeting molecules which could be used as vehicles for selective radionuclide delivery by virtue of their binding to MMPs. The aim of this work was to produce a radiopharmaceutical with which to evaluate this potential. The 127 amino acid N-terminal domain of recombinant human TIMP-2 (N-TIMP-2) was conjugated with the bifunctional chelator diethylenetriamine pentaacetic acid (DTPA). Singly modified DTPA-N-TIMP-2 conjugate (identified by electrospray ionization mass spectrometry) was isolated by anion-exchange chromatography. The primary site of DTPA modification on N-TIMP-2 was mapped to lysine-116, which is distant from the site of MMP interaction. The conjugate was radiolabeled with indium-111 to give 111In-DTPA-N-TIMP-2 with a specific activity of at least 4 MBq/microg and a radiochemical yield and purity of >95%, by incubation with 111InCl3, without need for postlabeling purification. The product was sterile, pyrogen-free, and stable in serum over 48 h and retained full inhibitory activity in a fluorimetric binding assay. With these attributes, 111In-DTPA-N-TIMP-2 is a suitable radiopharmaceutical for in vivo biological and clinical investigation of the potential benefits of imaging MMP expression.

Drug Design↗
PubMed2004

Brg-1 is required for maximal transcription of the human matrix metalloproteinase-2 gene.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases whose aberrant expression are correlated with tumor invasion and angiogenesis. The transcription factors Sp1, Sp3, and AP-2 are required for constitutive expression of MMP-2 in tumor cells; however, the regulatory mechanisms of MMP-2 expression are not well understood. We investigated the involvement of Brg-1, the ATPase subunit of the SWI/SNF complex, in human MMP-2 gene transcription. Reconstitution of Brg-1 enhances MMP-2 transcription in Brg-1-deficient SW-13 cells. Chromatin immunoprecipitation assay demonstrates that Brg-1 is required for recruitment of Sp1, AP-2, and polymerase II to the MMP-2 promoter, whereas the binding of Sp3 to the MMP-2 promoter is decreased upon Brg-1 reconstitution. Furthermore, Sp1 interacts with Brg-1 in vivo. Restriction enzyme accessibility assays indicate that accessibility of the MMP-2 promoter region is not changed in the absence or presence of Brg-1. These results illustrate the connection between the SWI/SNF complex and optimal expression of MMP-2 and highlight the critical function of Brg-1 in regulating the recruitment of Sp1, Sp3, AP-2, and polymerase II to the MMP-2 promoter.

Chromatin Assembly and Disassembly↗
PubMed2005

A small compound that inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-9 upregulation.

Matrix metalloproteinase-9 (MMP-9) is critically involved in the tumor invasion and metastasis processes. Since TNF-alpha plays a crucial role in the regulation of MMP-9 expression, the development of molecules capable of modulating TNF-alpha-induced signaling is an issue of concern. We identified a novel synthetic compound that inhibits TNF-alpha-induced MMP-9 upregulation in the HT1080 human fibrosarcoma cell line. The active compound SM-7368 inhibited TNF-alpha-induced MMP-9 upregulation in a concentration-dependent manner and showed maximal activity at 10 microM. SM-7368 inhibited TNF-alpha-induced MMP-9 mRNA transcript accumulation and protein expression. We also found that SM-7368 strongly inhibits TNF-alpha-induced NF-kappaB activity but not AP-1 activity. Moreover, we found that SM-7368 strongly inhibits the TNF-alpha-induced invasion of HT1080 human fibrosarcoma cell line. Taken together, our results demonstrate that SM-7368 is a synthetic compound that inhibits TNF-alpha-induced MMP-9 expression, and thus SM-7368 should be useful for the development of chemotherapies targeting TNF-alpha-mediated tumor invasion and metastasis.

Benzamides↗
PubMed2001

Loss of heterozygosity on chromosome 11q22-23 in melanoma is associated with retention of the insertion polymorphism in the matrix metalloproteinase-1 promoter.

Matrix metalloproteinase-1 (MMP-1, collagenase-1), which degrades interstitial collagen, is expressed at high levels by some tumor cells and is thought to enhance their invasiveness and metastatic potential. We recently described a common single nucleotide insertion polymorphism (2G allele) at -1,607 bp in the promoter of the MMP-1 gene that creates a binding site for the ETS family of transcription factors, and that is associated with enhanced transcription of this gene and increased enzyme activity. Allelic loss at the MMP-1 locus on chromosome 11 occurs in many tumors including melanoma, an invasive and aggressive cancer. We hypothesized that although loss of either the 1G or 2G allele from 1G/2G heterozygotes is random, retention of the transcriptionally more active 2G allele would favor tumor invasion and metastasis. As a result, a higher proportion of metastases would contain the 2G genotype than the 1G genotype. We report here the development of quantitative methods for assessing allelic loss at the MMP-1 locus, and demonstrate that 83% of the metastatic melanomas with loss of heterozygosity at this locus retained the 2G allele. This supports the hypothesis that retention of the 2G allele favors tumor invasion and metastasis in melanoma.

Adult↗
PubMed2000

Interaction between monocytes and vascular smooth muscle cells enhances matrix metalloproteinase-1 production.

Matrix metalloproteinase-1 (MMP-1) plays an important role in atherosclerotic plaque rupture. The purpose of this study was to investigate the expression of MMP-1 by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cells) were cocultured. MMP-1 levels were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescent labeled-collagen digestion. Immunohistochemistry was performed to determine which types of cells produce MMP-1. Adding THP-1 cells to VSMCs markedly increased the MMP-1 levels and activity of the culture media. MMP-1 levels were maximal when the cellular ratio of THP-1 cells/VSMCs was 1.0. Immunohistochemistry revealed that both types of cells in the coculture produced MMP-1. Separated coculture experiments showed that both direct contact and a soluble factor(s) contributed to MMP-1 production. Neutralizing anti-interleukin (IL)-6 and tumor necrosis factor-alpha antibodies inhibited coculture conditioned medium-induced MMP-1 production by VSMCs and THP-1 cells. Protein kinase C inhibitors, tyrosine kinase inhibitors, and a mitogen-activated protein kinase inhibitor significantly inhibited MMP-1 production by cocultures. Direct cell-to-cell interaction between THP-1 cells and VSMCs enhanced MMP-1 synthesis in both types of cells. Increased local MMP-1 production and activity induced by monocyte-VSMC interaction play an important pathogenic role in atherosclerotic plaque rupture.

Cell Adhesion↗