Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects.
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PMID:Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors. 1132 2

In skin biology, matrix metalloproteinases (MMPs) have been implicated in inflammatory matrix remodeling, neovascularization, wound healing and malignant transformation. Psoriasis is histologically characterized by keratinocyte hyperproliferation, infiltration of inflammatory cells, neoangiogenesis and production of cytokines, such as TNF-alpha, IL-1beta, TGF-alpha, and IFN-gamma, also capable of regulating MMP transcription. To investigate the role of stromelysins-1 and -2, matrilysin, metalloelastase, collagenases-1 and -3 and 92-kDa gelatinase as well as their inhibitors, TIMPs-1 and -3, in psoriasis, we performed in situ hybridization using 35S-labeled cRNA probes on 29 psoriatic lesions and 9 samples of normal looking skin from psoriatic patients. Metalloelastase mRNA was detected in 21/27 samples in macrophages that had migrated into the epidermis or in the inflammatory infiltrates of the superficial dermis. A quantity of 92-kDa gelatinase was found in macrophages and neutrophils (25/27). Stromelysin-1 mRNA was detected in basal keratinocytes in 4/21 lesions. Intracellular laminin-5 immunosignal in basal keratinocytes of the same samples, suggested that stromelysin-1 might participate in remodeling of the basement membrane zone. No signal for stromelysin-2 or collagenase-3 was found and only sweat glands were positive for matrilysin. TIMP-1 was more abundantly expressed than TIMP-3 in the inflammatory infiltrates and endothelial cells of dermal papillae (22/29). TIMP-3 was expressed perivascularly in 9/16 samples. Our results suggest that overexpression of the investigated MMPs by keratinocytes is not associated with psoriasis. However, macrophages express MMPs in psoriatic skin. Also TIMPs, particularly TIMP-1, were abundantly expressed, suggesting that mere MMP overexpression is unlikely to contribute to psoriatic tissue changes.
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PMID:Metalloelastase (MMP-12) and 92-kDa gelatinase (MMP-9) as well as their inhibitors, TIMP-1 and -3, are expressed in psoriatic lesions. 1138 Jun 13

Oesophageal adenocarcinoma is believed to arise from metaplastic mucosa in the distal oesophagus, a condition also known as Barrett's oesophagus (BE). BE develops as a result of injury caused by refluxing gastric and duodenal contents and is associated with increased risk of malignant transformation. Matrix metalloproteinases (MMPs) have been implicated in all aspects of tumour progression; tumour growth, basement membrane degradation, invasion and metastatic spread. Using in situ hybridization, we investigated the expression patterns of collagenases-1 and -3, stromelysin-2, matrilysin, metalloelastase and TIMPs-1 and -3 in BE, adenocarcinoma and lymph-node metastases. Matrilysin was expressed abundantly in 12/15 tumours and in 4/6 lymph-node metastases and its expression correlated with the histological aggressiveness of tumour. Matrilysin and metalloelastase were upregulated already in BE. Stromelysin-2 and collagenase-3 expression was detected only in a few tumours. Collagenase-1 was expressed by cancer and stromal cells in 9/15 tumours. Tumour-infiltrating macrophages expressed metalloelastase in 13/15 cancers. TIMPs-1 and -3 were expressed in 12/15 and 11/15 tumours, respectively. Laminin-5 and tenascin were abundantly expressed at the invasive front of poorly differentiated tumours, but not in BE. Our results indicate that matrilysin is the principal MMP expressed by tumour cells in oesophageal adenocarcinoma, and further studies are needed to investigate whether matrilysin or tenascin-C could be used as a predictive marker for progression of BE to cancer.
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PMID:Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma. 1148 70

The TIMP family of matrix metalloproteinase inhibitors consists of four members, of which TIMP-1, -2 and -4 are secreted, freely diffusible proteins, whereas TIMP-3 is ECM-associated. Mutations in the TIMP3 gene have been linked to Sorsby's fundus dystrophy (SFD), an autosomal dominant inherited retinal degenerative disease that leads to blindness. The SFD mutations characterized result in introduction of an unpaired cysteine residue in the C-terminal domain of TIMP-3. We have expressed four SFD mutant TIMP-3 proteins in baby hamster kidney (BHK) cells and evaluated their characteristics alongside wild-type TIMP-3. Analysis of the mutant proteins (Ser156Cys, Gly167Cys, Tyr168Cys and Ser181Cys) by SDS-PAGE and reverse zymography revealed that each of the mutants retained gelatinase A and gelatinase B inhibitory activity, and were localized to the ECM. Association rate constants for Ser156Cys TIMP-3 with gelatinase-A, gelatinase-B, stromelysin-1 and collagenase-3 were only moderately reduced compared to wild-type TIMP-3. However, all of the mutants displayed aberrant protein-protein interactions, resulting in the presence of additional proteins or complexes in ECM preparations. Two of the mutants (Ser156Cys and Ser181Cys) showed a marked propensity to form multiple higher molecular-weight complexes that retained TIMP activity on reverse zymography. Expression of the SFD mutant TIMP-3 (and to a lesser extent, wild-type TIMP-3) proteins in BHK cells conferred increased cell adhesiveness to the ECM. Our findings indicate that the pathogenesis of Sorsby's fundus dystrophy cannot be attributed to a failure to localize SFD TIMP-3 proteins to the ECM or defects in MMP inhibition, but may involve the formation of aberrant TIMP-3-containing protein complexes and altered cell adhesion.
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PMID:Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix. 1182 95

Matrix metalloproteinase-13 (MMP-13) is a proteolytic enzyme that belongs to a large family of extracellular matrix-degrading endopeptidases that are characterized by a zinc-binding motif at their catalytic sites. MMP-13 has a key role in the MMP activation cascade and appears to be critical in bone metabolism and homeostasis. It also has an important role in tumor invasion and metastasis. This commentary provides a detailed overview of the regulatory mechanisms, structure, and function of human MMP-13 and highlights the key factors involved in the biology of this important molecule.
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PMID:The structure, regulation, and function of human matrix metalloproteinase-13. 1213 41

Monocyte chemoattractant protein (MCP)-3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)-MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)-2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.
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PMID:Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. 1214 83

The role of various matrix metalloproteinases (MMP)--such as gelatinases, stromelysins, matrilysin, collagenase-3, and membrane-bound MMP (MB-MMP)--in tumor invasion and metastasis is discussed. Data suggesting significance for malignant growth of the expression level of these enzymes and also of their activators and inhibitors are presented. It is concluded that at different stages of tumor progression the activity of different MMPs is displayed, which is regulated by various growth factors and oncogenes. Different malignancies are characterized by changes in activities of specific MMPs. Data are presented which show significance of the ratio between the MMP activity and that of tissue inhibitors of metalloproteinases (TIMP) in tumor invasion and metastasis, especially in connection with a dual role of TIMP as both MMP inhibitors and activators.
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PMID:Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis. 1294 52

In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1alpha, IL-1beta, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1beta-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1beta-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.
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PMID:The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. 1598 75

Tears in the peripheral part of the menisci have a better healing potential than tears in the central part, because the central two-thirds of the menisci are avascular. The avascular status of the meniscus is maintained by the expression of antiangiogenic factors such as endostatin. The distribution of endostatin in the menisci correlates with the degree of vascularization. Endostatin immunostaining is strong in the avascular zone and reduced in the vascularized outer one-third. Endostatin interacts with signal transduction of the vascular endothelial growth factor (VEGF) by reducing VEGF-induced kinase (Erk1/2) phosphorylation. VEGF plays an important role in angiogenesis in fetal menisci and it is down-regulated in the adult meniscus. We hypothesized that healing of meniscal tears in the avascular zone can be promoted by the local application of the angiogenic factor VEGF. To evaluate this hypothesis a tear was created in the avascular zone of the medial meniscus in 18 merino sheep. The tear was then repaired with an uncoated suture (group 1), a suture coated with PDLLA (group 2), and by a suture coated with PDLLA/VEGF (group 3). After 6 weeks we observed increased factor VIII immunostaining in the VEGF-treated group. However, in this treatment group (VEGF/PDLLA) no meniscus healed. In the uncoated suture group and in the PDLLA-coated suture group partial healing was observed in three animals and complete healing in three animals, respectively. Factor VIII expression is normally restricted to vascular endothelial cells. In this study, however, single endothelial cells could be detected in the menisci of the VEGF/PDLLA group. This finding suggests that the application of VEGF might have stimulated proliferation of vascular endothelial cells but the application of VEGF was not successful in stimulating the more complex process of vasculogenesis. Further immunohistochemical examinations of the specimen have shown that in the VEGF/PDLLA group there is strong immunostaining against matrix metalloproteinase 13 (MMP-13). In vitro studies have shown that VEGF can stimulate chondrocytes to proliferate but also to express MMP-13 via HIF1-alpha induction. Since meniscal fibrochondrocytes express the VEGF receptor 2 (KDR) the induction of MMP expression might be another factor which inhibits healing despite increased angiogenesis. In conclusion, the local application of VEGF via PDLLA-coated sutures does not promote meniscal healing. A single growth factor might not always be a promising tool for the promotion of tissue repair. Further studies have to find out if growth factor combinations (VEGF and angiopoitin) might be more effective in stimulating vasculogenesis during meniscal healing.
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PMID:Locally applied angiogenic factors--a new therapeutic tool for meniscal repair. 1632 Aug 30

Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.
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PMID:Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. 1762 56


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