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

The small heat shock protein alphaB-crystallin is considered as a candidate autoantigen in multiple sclerosis (MS) lesions. Gelatinase B or matrix metalloproteinase (MMP)-9 is a proteinase establishing various disease-promoting feedback loops in autoimmune diseases. Human alphaB-crystallin was digested with natural gelatinase B and all cleavage sites were identified by a combined approach of mass spectrometry and peptide sequencing analysis. Previously identified immunodominant and cryptic epitopes of alphaB-crystallin in mice and rats were generated and largely left intact by MMP-9 processing. The alphaB-crystallin peptide 1-16, generated as a remnant epitope, provoked a significant T cell response in alphaB-crystallin knockout mice. None of the remnant peptides was encephalitogenic when injected intracerebrally into mice or induced MMP-9 in vitro. Gelatinase B is thus able to release T cell epitopes from intact alphaB-crystallin, but their pathogenic role remains unclear.
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PMID:A novel rationale for inhibition of gelatinase B in multiple sclerosis: MMP-9 destroys alpha B-crystallin and generates a promiscuous T cell epitope. 1296 53

Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown cause. Pathogenetic mechanisms, such as chemotaxis, subsequent activation of autoreactive lymphocytes, and skewing of the extracellular proteinase balance, are targets for new therapies. Matrix metalloproteinase gelatinase B (MMP-9) is upregulated in MS and was recently shown to degrade interferon beta, one of the drugs used to treat MS. Consequently, the effect of endogenously produced interferon beta or parenterally given interferon beta may be increased by gelatinase B inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and inhibition of hydroxymethyl-glutaryl-coenzyme-A reductase to lower expression of gelatinase B, may become effective treatments of MS, alone or in combination with interferon beta. This may allow interferon beta to be used at lower doses and prevent side-effects.
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PMID:Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis. 1463 80

Autoimmune diseases are characterized by inflammation and by the development and maintenance of antibodies and T lymphocytes against "self" antigens. Although the etiology of these diseases is unknown, they have a number of cellular and molecular mechanisms in common. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are upregulated and activate the inflammatory process. Chemokines recruit and activate leukocytes to release proteases, including matrix metalloproteinases (MMPs). These proteases degrade proteins into remnant fragments, which often constitute immunodominant epitopes. Either by direct loading into major histocompatibility complex (MHC) molecules or after classical antigen uptake, processing and MHC presentation, these remnant epitopes are presented to autoreactive T lymphocytes. Also, posttranslationally modified remnant peptides may stimulate B cells to produce autoantibodies. This forms the basis of the "Remnant Epitopes Generate Autoimmunity" (REGA) model. We have documented evidences for this model in multiple sclerosis (MS), rheumatoid arthritis (RA) and diabetes, which are summarized here. Furthermore, three topics will be addressed to illustrate the importance of glycobiology in the pathogenesis of autoimmune diseases. In MS, gelatinase B or MMP-9 is a pathogenic glycoprotein of which the sugars contribute to its interactions with the tissue inhibitor of metalloproteinases-1 (TIMP-1) and thus assist in the determination of the enzyme activity. In RA, gelatinase B cleaves denatured type II collagen into remnant epitopes, some of which constitute immunodominant glycopeptides. This implies that immunodominant epitope scanning experiments should preferably be done with natural posttranslationally modified glycopeptides, rather than with unmodified (synthetic) peptides. Sugars can also be used as molecular probes to induce autoimmune diseases. One of the best examples is the induction of acute pancreatitis, insulitis and diabetes by streptozotocin. In addition, gelatinase B is upregulated in pancreatitis and cleaves insulin. The most efficient cleavage by gelatinase B leads to a major insulin remnant epitope.
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PMID:Remnant epitopes generate autoimmunity: from rheumatoid arthritis and multiple sclerosis to diabetes. 1471 89

A polymorphism (PM) in the microsatellite of the promoter region of matrix metalloproteinase 9 (MMP-9), modulating its expression, could play a role in susceptibility to multiple sclerosis (MS). MMP-9 PM was determined in 95 patients with MS (MS Group) and 95 age- and sex-matched controls (Control Group). Comparison of allelic frequencies showed that a higher number of CA repeats characterized the MS group (P<0.0001) and prevalence of carriers of > or =22 CA repeats was higher in the MS than in the Control Group (OR 3.4, 95% CI: 1.7-6.8, P<0.0001). An earlier age at disease onset was a characteristic of patients with >22 CA repeats (33+/-10 vs. 28+/-10, P=0.027). No differences were found in the main MRI parameters.
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PMID:MMP-9 microsatellite polymorphism and multiple sclerosis. 1522 47

Matrix metalloproteinases, in particular gelatinase B/MMP-9, are key mediators in autoimmune diseases like multiple sclerosis and rheumatoid arthritis, but their pathogenic roles in diabetes are not well established. Gelatinase B has previously been shown to be upregulated in pancreas tissue from patients with acute and chronic pancreatitis and was suggested to exacerbate diabetes by cleaving insulin. In this study, the role of gelatinase B in diabetes was investigated using two streptozotocin-induced animal models of type I diabetes. In both a hyperacute and a subacute model, gelatinase B upregulation was found to be associated with disease activity. However, gelatinase B deficiency did not significantly protect against diabetes development, and wild-type and gelatinase B-deficient animals behaved similarly in terms of beta-cell apoptosis or necrosis. The fact that gelatinase B was found almost exclusively as the inactive pro-enzyme in most of the streptozotocin-induced diabetic animals may explain the lack of a gelatinase B effect. On the contrary, gelatinase B was completely activated in a minority (15%) of wild-type animals. This coincided with exocrine pancreatic inflammation, as revealed by the presence of active trypsin. The discovery of in vivo activation of progelatinase B by trypsin in acute pancreatitis is extended in a model of caerulein-induced pancreatitis. In the latter model, trypsinogen activation is systematically achieved and gelatinase B is found in its active form. In conclusion, gelatinase B itself is not a causative factor but, when activated by endogenous trypsin, is a permissive factor for insulin degradation and diabetes.
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PMID:In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes. 1553 38

In multiple sclerosis (MS), the matrix metalloprotease (MMP) gelatinase B/MMP-9 and platelet endothelial cell adhesion molecule (PECAM)-1 have both been implicated in trans-endothelial infiltration of leucocytes into the brain, but their functional connection has not yet been investigated. We investigated the expression of gelatinase B and PECAM-1 in post mortem brains of MS patients by immunohistochemistry. Because increased soluble PECAM-1 serum levels have been observed in MS patients, we also tested in vitro whether this could be due to cleavage of PECAM-1 by gelatinase B or matrilysin-1/MMP-7. Constitutive expression of PECAM-1 was found on brain endothelial cells, whilst in active MS lesions cell-bound PECAM-1 was highly up-regulated on foamy macrophages in perivascular infiltrates and co-localized with gelatinase B. However, human THP-1 monocyte-bound or soluble recombinant PECAM-1 were both resistant to proteolytic cleavage by gelatinase B or matrilysin-1 in vitro, as demonstrated by Western blot analysis and flow cytometry. These results suggest that PECAM-1 and gelatinase B may complement each other during the transmigration of the blood-brain barrier by mononuclear cells.
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PMID:PECAM-1 and gelatinase B coexist in vascular cuffs of multiple sclerosis lesions. 1640 49

The role of extracellular proteolysis in innate and adaptive immunity and the interplay between cytokines, chemokines and proteinases are gradually becoming recognized as critical factors in autoimmune processes. Many of the involved proteinases, including those of the plasminogen activator and matrix metalloproteinase cascades, and also several cytokines and chemokines, are glycoproteins. The stability, interactions with inhibitors or receptors, and activities of these molecules are fine-controlled by glycosylation. We studied gelatinase B or matrix metalloproteinase-9 (MMP-9) as a glycosylated enzyme involved in autoimmunity. In the joints of rheumatoid arthritis patients, CXC chemokines, such as interleukin-8/CXCL8, recruit and activate neutrophils to secrete prestored neutrophil collagenase/MMP-8 and gelatinase B/MMP-9. Gelatinase B potentiates interleukin-8 at least tenfold and thus enhances neutrophil and lymphocyte influxes to the joints. When cartilage collagen type II is cleaved at a unique site by one of several collagenases (MMP-1, MMP-8 or MMP-13), it becomes a substrate of gelatinase B. Human gelatinase B cleaves the resulting two large collagen fragments into at least 33 peptides of which two have been shown to be immunodominant, i.e., to elicit activation and proliferation of autoimmune T cells. One of these two remnant epitopes contains a glycan which is important for its immunoreactivity. In addition to the role of gelatinase B as a regulator in adaptive immune processes, we have also demonstrated that it destroys interferon-beta, a typical innate immunity effector molecule and therapeutic cytokine in multiple sclerosis. Furthermore, glycosylated interferon-beta, expressed in Chinese hamster ovary cells, was more resistant to this proteolysis than recombinant interferon-beta from bacteria. These data not only prove that glycosylation of proteins is mechanistically important in the pathogenesis of autoimmune diseases, but also show that targeting of glycosylated proteinases or the use of glycosylated cytokines seems also critical for the treatment of autoimmune diseases.
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PMID:Remnant epitopes, autoimmunity and glycosylation. 1643 62

Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in an array of physiological and pathological processes from development, morphogenesis, reproduction, wound healing, and aging to inflammation, angiogenesis, neurological disorders, and cancer cell invasion and metastasis. The imbalance between MMP activity and the inhibitory action of tissue inhibitors of metalloproteinases (TIMPs) are implicated in multiple diseases. Secreted in the body in a latent form, upon activation MMP-9 (gelatinase B) acts on many inflammatory substrates, and thus is suspected of contributing to the progression of cardiovascular disease, rheumatoid arthritis, and the subjects of this review, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS). COPD is the fourth most common cause of death in the United States. In COPD, increased expression of MMP-9 by inflammatory cells e.g. neutrophils and macrophages is correlated with a variety of processes that cause lung damage. MMP-9 is also important in cytokine and protease modulation; it degrades the serine protease inhibitor alpha(1)-antitrypsin, which thus may lead to lung destruction. MS affects approximately 400,000 Americans and over a million people worldwide. Upregulation of MMP-9 increases the permeability of the blood brain barrier (BBB), facilitates the infiltration of leukocytes into the central nervous system, and causes myelin sheath degradation and neuronal damage. Early stage clinical trials have shown promising results when MMP-9 is inhibited in MS. These observations lead to the hypothesis that MMP-9 is a potential drug target for both COPD and MS and further development of highly potent and specific MMP-9 inhibitors is warranted.
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PMID:Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis. 1828 55

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-gamma, TNF-alpha, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-gamma and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.
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PMID:Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. 1949 26

Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl-N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents.
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PMID:In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors. 2238 84


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