EC:3.4.24.35 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SPARC (secreted protein, acidic and rich in cysteine), also called osteonectin or BM-40, is a collagen-binding glycoprotein secreted by a variety of cells and is associated with functional responses involving tissue remodeling, cell movement and proliferation. Because SPARC and monocytes/macrophages are prevalent at sites of inflammation and remodeling in which there is connective tissue turnover, we examined the effect of SPARC on monocyte matrix metalloproteinase (MMP) production. Treatment of human peripheral blood monocytes with SPARC stimulated the production of gelatinase B (MMP-9) and interstitial collagenase (MMP-1). Experiments with synthetic peptides indicated that peptide 3.2, belonging to the alpha helical domain III of SPARC, is the major peptide mediating the MMP production by monocytes. SPARC and peptide 3.2 were also shown to induce prostaglandin synthase (PGHS)-2 as determined by Western and Northern blot analyses. The increase in PGHS-2 stimulated by SPARC or peptide 3.2 correlated with substantially elevated levels of prostaglandin E2 (PGE2) and other arachidonic acid metabolites as measured by radioimmunoassay and high performance liquid chromatography (HPLC), respectively. Moreover, the synthesis of MMP was dependent on the generation of PGE2 by PGHS-2, since indomethacin inhibited the production of these enzymes and their synthesis was restored by addition of exogenous PGE2 or dibutyryl cAMP (Bt2cAMP). These results demonstrate that SPARC might play a significant role in the modulation of connective tissue turnover due to its stimulation of PGHS-2 and the subsequent release of PGE2, a pathway that leads to the production of MMP by monocytes.
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PMID:Regulation of human monocyte matrix metalloproteinases by SPARC. 936 45

Psoriasis is histologically characterized by hyperkeratosis and papillomatosis with elongated vessels in the upper dermis. In order to evaluate the role of gelatinases in remodelling psoriatic skin in this study we examined the production of the 72-kDa (gelatinase A), 92-kDa collagenase (gelatinase B) and their tissue inhibitors TIMP-2 and TIMP-1. A total of 19 patients affected by different types of psoriasis were included in this study. An immunohistochemical study on cryosections was performed using antibodies to 72-kDa gelatinase, 92-kDa gelatinase, TIMP-1, TIMP-2, laminin, collagen types I, III, IV, VII. mRNA expression for gelatinases and their inhibitors were also analyzed by reverse transcriptase polymerase chain reaction (RT-PCR). In 14 of 19 patients there was a positivity in 92-kDa protein expression in keratinocytes. The 92-kDa gelatinase protein was also present in the upper dermis with prevalence around blood vessels. In 15 of 19 patients the 72-kDa was localized in the upper dermis, almost exclusively in the papillary dermis but absent in epidermis. TIMP-1 and TIMP-2 were both negative in all cases in immunoperoxidase and RT-PCR. Using RT-PCR we show that the 72-kDa mRNA is expressed exclusively in the dermis, on the contrary the 92-kDa was present in epidermis and dermis. Type I, III, IV and VII collagens did not show any alteration or disruption. Overexpression and production of gelatinases without inhibitory effects suggest a role of these proteins in remodelling the psoriatic skin probably inducing the typical histological pattern of papillomatosis.
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PMID:The 72-kDa and the 92-kDa gelatinases, but not their inhibitors TIMP-1 and TIMP-2, are expressed in early psoriatic lesions. 941 21

Interleukin-1 (IL-1) greatly induces osteoclast formation and stimulates bone resorption of mouse calvaria in culture. In the presence of soluble IL-6 receptor (sIL-6R), IL-6 similarly induces osteoclast formation, but the potency of IL-6 in inducing bone resorption in organ culture is weaker than that of IL-1. To study the differences in bone-resorbing activity between IL-1 and IL-6, we examined the effects of the two cytokines on the induction of matrix metalloproteinases (MMPs). In mouse calvarial cultures, IL-1 markedly enhanced the messenger RNA (mRNA) expression of MMP-13 (collagenase 3), MMP-2 (gelatinase A), MMP-9 (gelatinase B), and MMP-3 (stromelysin 1), which associated with increases in bone matrix degradation. A hydroxamate inhibitor of MMPs significantly suppressed bone-resorbing activity induced by IL-1. Gelatin zymography showed that both pro- and active-forms of MMP-2 and MMP-9 were detected in the conditioned medium collected from calvarial cultures, and IL-1 markedly stimulated both pro- and active-forms of the two gelatinases. IL-6 with sIL-6R also stimulated mRNA expression and biological activities of these MMPs, but the potency was much weaker than that of IL-1. Conditioned medium collected from IL-1-treated calvariae degraded native type I collagen, but 3/4- and 1/4-length collagen fragments were not detected, suggesting that both collagenases and gelatinases synergistically degraded type I collagen into smaller fragments. In mouse osteoblastic cells, the expression ofMMP-2, MMP-3, and MMP-13 mRNAs could be detected, and they were markedly enhanced by IL-1alpha on days 2 and 5. IL-6 with sIL-6R also induced expression of MMP-13 and MMP-2 mRNAs on day 2, but the expression was rather transient. These results demonstrate that the potency of induction of MMPs by IL-1 and IL-6 is closely linked to the respective bone-resorbing activity, suggesting that MMP-dependent degradation of bone matrix plays a key role in bone resorption induced by these cytokines.
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PMID:Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. 949 70

Human extracellular matrix is constantly remodelled by de novo synthesis of structural components and by degradation of the matrix proteins by various proteinases. The secreted proteolytic enzymes are regulated at several levels: by control of gene transcription, by glycosylation, by specific inhibitors and by enzyme activation processes. The latter level most often involves clipping of a proenzyme or zymogen into an active proteinase. A series of such activation reactions leads to enzyme cascades. Whereas proteolytic activation is an all-or-none phenomenon, glycosylation usually has a restricted or fine-tuning effect on the catalytic activity of enzymes. Commonly, a two- to threefold reduction in specific activity is imposed by N-glycosylation on each member of the multi-enzyme chain. In a series comprising e.g. four enzymes, this can lead to significant influences (2(4)-3(4)-fold increase) on the substrate converting activity of the terminal member of a cascade. Gelatinase B is a terminal member of the protease cascade which leads to matrix degradation. It cleaves gelatins (denatured collagens or collagen fragments after digestion by collagenase) and other substrates and is thought to be involved in matrix remodeling during the normal processes of embryogenesis, tissue remodeling and development. Gelatinase B expression is upregulated in pathological states such as invasion of cancer cells and when leukocytes are released from the bone marrow and migrate towards an inflammatory focus. Proteases, including gelatinase B, are transcriptionally regulated by cytokines and directly by the activation processes. The gene regulation of enzyme inhibitors as well as other humoral factors, which contribute to protease activation, influence protease activities in an indirect way. Proteases might also play a role in the pathophysiology of chronic inflammation and autoimmunity by cleaving extracellular structural proteins and by generating proteolytic fragments. Indeed, these remnant fragments antigenically resemble the original precursor proteins, but are structurally and quantitatively different and may provoke an autoimmune response. Application of the knowledge of the structure, function and regulation of gelatinase B has contributed to the understanding of the mechanism of action of some gelatinase-inhibiting antirheumatic drugs and promises to contribute further to the development of novel treatment strategies for autoimmune diseases such as multiple sclerosis and for invasive cancers.
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PMID:On the roles of extracellular matrix remodeling by gelatinase B. 954 20

Gelatinase B (matrix metalloproteinase-9) is able to degrade several extracellular matrix proteins, including gelatin, elastin, and collagen types IV, V, XI, and XIV. This enzyme contains a "fibronectin-like" domain which is composed of three tandem copies of a fibronectin type 2 homology unit inserted into its catalytic domain. We have studied the involvement of this domain in the substrate specificity of gelatinase B by expressing a mutant of the enzyme, in Escherichia coli, in which this domain has been deleted. This mutant enzyme retained its ability to cleave the peptide substrate Mca-PLGL(Dpa)AR-NH2, possessing K(m) and kcat values similar to those of the wild-type enzyme. In addition, the NH2-terminal, 14-kDa, inhibitory domain of recombinant tissue inhibitor of metalloproteinase-2 was able to inhibit the mutant and the wild-type enzymes with the same potency. The mutant's gelatinolytic activity was also retained but reduced in comparison to that of the wild-type enzyme. However, contrary to the wild-type enzyme, the mutant was not able to digest or bind fibrillar collagen types V and XI. These data indicate that the fibronectin-like domain of gelatinase B is an important determinant of the enzyme's fibrillar collagen substrate specificity. It allows the enzyme to bind to and cleave collagen types V and XI, events which are thought to be involved in several normal physiological and pathological processes such as metastasis and arthritis.
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PMID:The fibronectin-like domain is required for the type V and XI collagenolytic activity of gelatinase B. 963 94

In interstitial lung diseases, deposition of extracellular matrix (ECM) in alveoli and degradation of ECM lead to pulmonary structural remodeling. The changes in ECM and the localization of matrix metalloproteinases (MMPs) and a tissue inhibitor of metalloproteinases (TIMP) in the lung tissues of patients with bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pulmonary fibrosis (IPF) were investigated. Immunohistochemical analysis for the detection of fibronectin, collagen-I, -III, and -IV, smooth muscle actin, MMP-1 (interstitial collagenase), -2 (gelatinase A), and -9 (gelatinase B), and TIMP-2, and in situ hybridization for the detection of MMP-9 mRNA were performed. Western blotting of lung tissue homogenates was performed for MMP-2 and MMP-9. The gelatinolytic activities of the homogenates were also determined using gelatin zymography. Fibronectin and collagen-I, -III, and -IV were detected in the intra-alveolar fibrosis in addition to the interstitium of these diseases. MMP-1, MMP-2, MMP-9, and TIMP-2 were detected in the regenerated epithelial cells covering intra-alveolar fibrosis. Myofibroblasts in intra-alveolar fibrosis in BOOP showed predominant reaction for MMPs, and they ultrastructurally appeared to be phagocytosing collagen fibrils, and those of IPF showed a predominant reaction for TIMP-2. New vascularization in intra-alveolar fibrosis was exclusively observed in cases of BOOP, and the endothelial cells were positive for MMP-2. Western blotting showed the existence of a latent form of MMP-9 and latent and active forms of MMP-2, and gelatin zymography revealed that the ratio of active/latent forms of MMP-2 in BOOP is significantly larger than that in the control lungs. Predominant MMPs in BOOP may constitute the mechanism of reversibility of fibrotic changes in this disease. TIMP-2 in myofibroblasts in IPF may contribute to the stable ECM deposition and the irreversible pulmonary structural remodeling.
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PMID:Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. 964 59

Chondrocytes cultivated in monolayer rapidly divide and lose their morphological and biochemical characteristics, whereas they maintain their phenotype for long periods of time when they are cultivated in alginate beads. Because cartilage has a low cellularity and is difficult to obtain in large quantities, the number of available cells often becomes a limiting factor in studies of chondrocyte biology. Therefore, we explored the possibility of restoring the differentiated properties of chondrocytes by cultivating them in alginate beads after two multiplication passages in monolayer. This resulted in the reexpression of the two main markers of differentiated chondrocytes: Aggrecan and type II collagen gene expression was strongly reinduced from day 4 after alginate inclusion and paralleled protein expression. However, 2 weeks were necessary for total suppression of type I and III collagen synthesis, indicators of a modulated phenotype. Interleukin-1beta, a cytokine that is present in the synovial fluid of rheumatoid arthritis patients, induces many metabolic changes on the chondrocyte biology. Compared with cells in primary culture, the production of nitric oxide and 92-kDa gelatinase in response to interleukin-1beta was impaired in cells at passage 2 in monolayer but was fully recovered after their culture in alginate beads for 2 weeks. This suggests that the effects of interleukin-1beta on cartilage depend on the differentiation state of chondrocytes. This makes the culture in alginate beads a relevant model for the study of chondrocyte biology in the presence of interleukin-1beta and other mediators of cartilage destruction in rheumatoid arthritis and osteoarthrosis.
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PMID:Dedifferentiated chondrocytes cultured in alginate beads: restoration of the differentiated phenotype and of the metabolic responses to interleukin-1beta. 964 17

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by deposition of autoantibodies at the basement membrane zone. In an experimental BP model in mice, the subepidermal blistering is mediated by antibodies directed against the hemidesmosomal protein BP180 (collagen XVII, BPAG2), and depends on complement activation and neutrophil infiltration. Gelatinase B is present in BP blister fluid and can cleave BP180. In this study we investigated the role of gelatinase B in the immunopathogenesis of experimental BP using mice containing targeted disruption of the gelatinase B (MMP-9, 92 kD gelatinase) gene. Gelatinase B-deficient mice were resistant to the blistering effect of intracutaneous anti-mBP180 antibodies, although these mice showed deposition of autoantibodies at the basement membrane zone and neutrophil recruitment to the skin comparable to that observed in the control mice. Interleukin 8 given intradermally concomitantly with pathogenic anti-mBP180 elicited a significant neutrophil recruitment into the skin in gelatinase B-deficient mice, but blistering did not occur. However, gelatinase B-deficient mice reconstituted with neutrophils from normal mice developed blistering in response to anti-mBP180 antibodies. These results implicate neutrophil-derived gelatinase B in the pathogenesis of experimental BP and might lead to novel therapeutic strategies for BP.
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PMID:Gelatinase B-deficient mice are resistant to experimental bullous pemphigoid. 968 25

Matrix metalloproteinases (MMPs) have been reported to be involved in inflammatory disorders of the central nervous system (CNS). However, little is known about the role of MMPs in the pathogenesis of HTLV-I-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). To address this issue, we examined the tissue expression and localization of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) in the spinal cord lesions of HAM/TSP using immunohistochemistry. In addition, the blood and cerebrospinal fluid (CSF) levels of MMPs and TIMPs of the patients with HAM/TSP were determined using sandwich enzyme immunoassays (SIA) and gelatin zymography. Immunohistochemical studies revealed that collagen IV and decorin immunoreactivity on the basement membrane of CNS parenchymal vessels was partially disrupted where inflammatory mononuclear cells infiltrated in active-chronic lesions of HAM/TSP. In these lesions, MMP-2 (gelatinase A) was immunostained mainly on the surface of foamy macrophages and lymphocytes, whereas MMP-9 (gelatinase B) expression was positive in the intravascular and perivascular mononuclear cells but not on foamy macrophages. In contrast, inactive chronic lesions of the spinal cords of the HAM/TSP contained fewer MMP-2-positive or MMP-9-positive mononuclear cells than active-chronic lesions. Many parenchymal vessels had thickened vascular walls which showed increased immunoreactivity to decorin. SIA revealed that production levels of MMP-2 and MMP-9 in both blood and CSF were higher in the patients with HAM/TSP than those in non-inflammatory other neurological disease controls (ONDs). Using zymography, proMMP-9 was detected more frequently in the CSF of patients with HAM/TSP than those in ONDs. Taken together, our data indicate that MMP-2 and MMP-9 may play an important role in the blood-brain barrier breakdown and tissue remodeling in the CNS of HAM/TSP.
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PMID:Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in HTLV-I-associated myelopathy. 973 47

A metastatic rat mammary carcinoma cell line, BC1, contains cells that have retained epithelial differentiation characteristics and metaplastic cells that have undergone an epithelial-mesenchymal transition. These two subpopulations cooperate to degrade collagen. We have used novel PCR assays to quantitate, for the first time, absolute levels of the mRNAs encoding matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cell and tumor samples. BC1 tumors expressed high levels of the collagenase-3, TIMP-2, stromelysin-1, and gelatinase B genes and low levels of the stromelysin-2 and TIMP-1 genes. This pattern of expression was repeated in cultures of BC1 and cultures containing mixed clones of epithelial cells and metaplastic cells. In both BC1 and the biclonal cultures, metaplastic cells were the main source of collagenase-3, stromelysin-1 and stromelysin-2, whereas TIMPs were equally distributed and epithelial cells were the main source of gelatinase B. High levels of all four MMP mRNAs in metaplastic cells were dependent on coculture with epithelial cells, suggesting the production of an inducing factor by the epithelial cells. In contrast, gelatinase B mRNA was produced at a high level by epithelial cells in the absence of metaplastic cells. TIMP-2 mRNA was abundant in both subpopulations grown alone and did not change substantially upon coculture. Thus, the interclonal cooperativity to degrade collagen in BC1 cells required the induction of MMPs in metaplastic cells by epithelial cells. Interclonal cooperativity may be important to the progression of neoplastic tumors, a feature of which is phenotypic heterogeneity.
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PMID:Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. 981 7

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