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)

Tissue inhibitors of matrix metalloproteinases (TIMPs) represent a family of ubiquitous proteins which main biological function resides in their ability to control the activity of matrix metalloproteinases (MMPS). The structures and specificities of TIMP1 and TIMP2 are described. Moreover, TIMP1, but not TIMP2, is able to stimulate the growth of several cell types. TIMP1 interacts with keratinocytes via a receptor mediated pathway (Kd = 8.7 nM; 135,000 sites/cell). Thus, this inhibitor does contain several structural domains able to recognize i) MMP active site, ii) pro-MMP9 hemopexin-like domain, iii) cell membrane proteins.
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PMID:[Tissue inhibitors of matrix metalloproteinases TIMP 1-2. Structures and functions]. 801

Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs) implicated in normal and pathological processes that require remodelling of the extracellular matrix. In human prostate tissue, matrilysin is synthesized in ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but not in normal glands. Gelatinase B expression is restricted to inflammatory cells. Gelatinase A can be found in both benign and malignant prostate tissue. MMP activities are regulated by their transition from latent to activated forms, as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We investigated whether matrilysin can activate progelatinases A and B in the presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS-PAGE and enzyme activity assays. TIMP-free gelatinase B was also activated by matrilysin. In addition, activation of progelatinase B by matrilysin was demonstrated in the conditioned medium of phorbol ester-treated HT1080 cells, confirming the results obtained in the in vitro experiments. In contrast, matrilysin did not proteolytically cleave gelatinase A-TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Matrilysin did not enhance the autocatalytic conversion of its own proform. The data presented here suggest that matrilysin participates in a proteolytic cascade and can activate gelatinases in the presence of TIMPs.
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PMID:Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by matrilysin. 956 Mar 29

Fibroblast contraction in wound healing involves the interaction of several cell types, cytokines, and extracellular matrix molecules. We have previously developed fibroblast alignment models using precise uniaxial mechanical loads in 3D culture and using contact guidance on fibronectin strands. Our aim here was to use contact guidance to place fibroblasts in their potentially most sensitive configuration, i.e., perpendicular to the axis of loading, to present cells with conflicting guidance cues. Gene expression at the mRNA level of cells recovered from different zones of the 3D collagen gel (with distinct orientation) was determined by quantitative RT-PCR for the matrix proteases MMP1, 2, and 3, and inhibitors TIMP1 and 2. Our results show a 2-, 4-, and 3-fold increase in MMP1, 2, and 3, respectively, in the non-aligned strain zone, relative to the aligned strain zone. These results suggest that cells unable to align to applied loads remodel their matrix far more rapidly than orientated cells. Where fibroblasts were held in an alignment perpendicular to the applied load by contact guidance, the fall in MMP mRNA expression was largely abolished, indicating that these cells remained in a mechano-activated state. The protease inhibitors TIMP1 and 2 were poorly mechano-responsive, further suggesting that changes in MMP expression result in functional matrix remodelling. These results indicate how mechanical loading in tissues may influence matrix remodelling, particularly under conflicting guidance cues.
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PMID:Molecular responses of human dermal fibroblasts to dual cues: contact guidance and mechanical load. 1061 62

Membrane type 4 matrix metalloproteinase (MT4-MMP) shows the least sequence homology to the other MT-MMPs, suggesting a distinct function for this protein. We have isolated a complete cDNA corresponding to the mouse homologue which includes the signal peptide and a complete pro-domain, features that were lacking from the human form originally isolated. Mouse MT4-MMP (mMT4-MMP) expressed in COS-7 cells is located at the cell surface but does not show ability to activate pro-MMP2. The pro-catalytic domain was expressed in Escherichia coli as insoluble inclusions and active enzyme recovered after refolding. Activity of the isolated catalytic domain against synthetic peptides commonly used for MMP enzyme assays could be inhibited by TIMP1, -2, and -3. The recombinant mMT4-MMP catalytic domain was also unable to activate pro-MMP2 and was very poor at hydrolyzing components of the extracellular matrix with the exception of fibrinogen and fibrin. mMT4-MMP was able to hydrolyze efficiently a peptide consisting of the pro-tumor necrosis factor alpha (TNFalpha) cleavage site, a glutathione S-transferase-pro-TNFalpha fusion protein, and was found to shed pro-TNFalpha when co-transfected in COS-7 cells. MT4-MMP was detected by Western blot in monocyte/macrophage cell lines which in combination with its fibrinolytic and TNFalpha-converting activity suggests a role in inflammation.
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PMID:Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. 1079 78

Matrix metalloproteinase (MMPs) are critical for the degradation of extracellular matrix components and, therefore, need to be regulated tightly. Almost all MMPs share a homologous C-terminal haemopexin-like domain (PEX). Besides its role in macromolecular substrate processing, the PEX domains appear to play a major role in regulating MMP activation, localisation and inhibition. One intriguing property of MMP9 is its competence to bind different proteins, involved in these regulatory processes, with high affinity at an overlapping recognition site on its PEX domain. With the crystal structure of the PEX9 dimer, we present the first example of how PEX domains accomplish these diverse roles. Blade IV of PEX9 mediates the non-covalent and predominantly hydrophobic dimerisation contact. Large shifts of blade III and, in particular, blade IV, accompany the dimerisation, resulting in a remarkably asymmetric homodimeric structure. The asymmetry provides a novel mechanism of adaptive protein recognition, where different proteins (PEX9, PEX1, and TIMP1) can bind with high affinity to PEX9 at an overlapping site. Finally, the structure illustrates how the dimerisation generates new properties on both a physico-chemical and functional level.
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PMID:Structural basis of the adaptive molecular recognition by MMP9. 1212 25

This study analyzes the molecular response of articular chondrocytes to short-term mechanical loading with a special focus on gene expression of molecules relevant for matrix turnover. Porcine cartilage explants were exposed to static and dynamic unconfined compression and viability of chondrocytes was assessed to define physiologic loading conditions. Cell death in the superficial layer correlated with mechanical loading and occurred at peak stresses >or=6 MPa and a cartilage compression above 45%. Chondrocytes in native cartilage matrix responded to dynamic loading by rapid and highly specific suppression of collagen expression. mRNA levels dropped 11-fold (collagen 2; 6 MPa, P=0.009) or 14-fold (collagen 1; 3 and 6 MPa, P=0.009) while levels of aggrecan, tenascin-c, matrix metalloproteinases (MMP1, 3, 13, 14), and their inhibitors (TIMP1-3) did not change significantly. Thus, dynamic mechanical loading rapidly shifted the balance between collagen and aggrecan/tenascin/MMP/TIMP expression. A better knowledge of the chondrocyte response to mechanical stress may improve our understanding of mechanically induced osteoarthrits.
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PMID:Rapid regulation of collagen but not metalloproteinase 1, 3, 13, 14 and tissue inhibitor of metalloproteinase 1, 2, 3 expression in response to mechanical loading of cartilage explants in vitro. 1255 75

Autoimmune diseases are either tissue-specific like multiple sclerosis (MS) or multisystemic like systemic lupus erythematosus (SLE), although clinically both exhibit common features. To gain insight into the properties of the genes involved in each disease we have investigated the gene expression signature of peripheral blood mononuclear cells (PBMC) in MS and SLE in comparison to healthy subjects. Total RNA was purified, hybridized to Genechip array and analysed in 36 subjects (13 relapsing-remitting MS patients, five SLE patients and 18 age-matched healthy subjects that served as controls). Additional blood samples from 15 relapsing-remitting MS patients, 8 SLE patients and 10 healthy subjects were used for confirmation of microarray gene expression findings by ELISA and RT-PCR. MS and SLE patients demonstrated a common gene expression autoimmune signature of 541 genes which differentiated them from healthy subjects. The autoimmune signature included genes that encode proteins involved in apoptosis, cell cycle, inflammation and regulation of matrix metalloproteinase pathways. Specifically, decreased TIMP1 gene expression in the autoimmunity signature suggests increased MMP activity in target tissues as a result of the lack of feedback mechanism. An additional different disease specific signature identified the gene expression pattern for MS (1031 genes), mainly associated with over-expression of adhesion molecules and down-expression of heat shock proteins; the SLE specific signature (1146 genes) mainly involved DNA damage/repair pathways that result in production of nuclear autoantibodies. These results provide insights into the genetic pathways underlying autoimmune diseases, and identify specific disease-associated signatures that may enable targetted disease-related specific therapies to be developed.
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PMID:Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus. 1537 20

Supravalvular aortic stenosis (SVAS) and Williams Beuren syndrome (WBS) can be considered as inherited diseases affecting the whole arterial tree and causing narrowing of the vessels. It has been reported that abnormal deposition of elastin in arterial walls of patients with SVAS and WBS leads to increased proliferation of arterial smooth muscle cells (SMC), which result in the formation of hyperplastic intimal lesions. In this work, we conducted morphological and morphometrical analysis with stenotic aortas from patients suffering from SVAS and WBS and from healthy control subjects and demonstrated that the amount of elastic fibers and the loss of integrity of vascular elastic fibers in the aortas reflect similar changes in the skin of patients with SVAS or WBS, as reported in our previous work conducted on skin in these pathological states. On the other hand, we conducted investigations on metalloproteinases (MMP2, MMP9, MMP7) and their specific tissue inhibitors TIMP1 and TIMP2 to verify their possible involvement in the etiopathogeny of SVAS and WBS. We particularly evidenced an altered MMP9/TIMP1 balance in favor of matrix degradation which could facilitate SMC migration and neointimal hyperplasia. Our findings suggest that elastinolytic enzymes secreted by arterial SMC, possibly including matrilysin 1, are critical for the development of arterial lesions in SVAS and WBS and contribute to perpetuate arterial stenosis in either SVAS or WBS.
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PMID:Vascular wall remodeling in patients with supravalvular aortic stenosis and Williams Beuren syndrome. 1583 55

Asbestos is a known inflammatory, carcinogenic, and fibrotic agent, but the mechanisms leading to asbestos-induced lung diseases are unclear. Using a murine inhalation model of fibrogenesis, we show that asbestos causes significant increases in mRNA levels of lung matrix metalloproteinases (MMPs 12 and 13) and tissue inhibitor of metalloproteinases (TIMP1), as well as increased activities of MMP 2, 9, and 12 in bronchoalveolar lavage fluids (BALF). Asbestos-exposed PKCdelta knockout (PKCdelta-/-) mice exhibited decreased expression of lung MMP12 and MMP13 compared with asbestos-exposed wild-type mice. Studies using small molecule inhibitors in murine alveolar epithelial type II cells (C10) and primary lung fibroblasts confirmed that asbestos transcriptionally up-regulates MMPs via an EGFR (or other growth factor receptors)/PI3K/PKCdelta/ERK1/2 pathway. Moreover, use of a broad-spectrum MMP inhibitor showed that MMPs play an important role in further enhancing asbestos-induced signaling events by activating EGFR. These data reveal a potentially important link between asbestos signaling and integrity of the extracellular matrix (ECM) that likely contributes to asbestos-induced lung remodeling and diseases.
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PMID:Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCdelta-dependent pathway in murine lung. 1657 79

In recent years, significant progress was made, particularly through the use of the macaque monkey, in identifying three types of local factors that are induced by the midcycle LH surge and play a critical role in ovulation and/or luteinization of the primate follicle. The ovulatory gonadotropin surge increases prostaglandin (PTG, typically abbreviated PG) levels in follicles prior to rupture; although considerable attention has focused on LH stimulation of the "inducible" form of PG G/H synthase (PTGS2), other aspects of PG synthesis (notably a phospholipase A2, cPLA2, and a PGE synthase, PTGES) and metabolism (15-hydroxy PG dehydrogenase, HPGD) also appear LH-regulated and may control the timing of the PG rise in the ovulatory follicle. Local (intrafollicular) ablation and replacement of PGs suggests that PGE2 is essential for release of the oocyte; but not necessarily for follicle rupture, and not for luteinization. Novel PGE-regulated genes are being identified in macaque granulosa cells, including adipose differentiation-related protein (ADFP). Similar types of studies indicate that the rise in progesterone (P) synthesis, as well as the induction of the genomic P receptor in granulosa cells, is essential for both ovulation and luteinization of the primate follicle. Limited data suggest that P action controls cell cycle activity (via cyclin B1 and cyclin-dependent kinase inhibitor p27), cholesterol uptake and utilization (e.g., low density lipoprotein or LDL receptor), proteases and their inhibitors (matrix metalloproteinase or MMP1; tissue inhibitor of MMP or TIMP1) and cell health in the granulosa cell layer. Finally, members of two classes of angiogenic factors, originally proposed as important for embryonic and pathologic (tumorigenic) vasculogenesis, appear induced in the granulosa layer of the preovulatory follicle, i.e., vascular endothelial growth factor (VEGF) and angiopoietin (ANGPT). Local injection of antagonists to VEGF (soluble VEGF receptor) and ANGPT (the natural antagonist ANGPT2) into the preovulatory follicle suppressed ovulation and luteinization in monkeys, possibly by disrupting the structure-function of existing vessels or preventing angiogenesis in the avascular granulosa layer. Further studies using high-throughput genomic and proteomic analysis, particularly on specific cell types (e.g., granulosa, theca and microvascular cells) and distinct follicular regions (apex, base and cumulus-oocyte complex) of the dominant follicle in natural menstrual cycles, are needed. Such information is essential to advance our understanding of the cascade of events leading to ovulation and luteinization of the primate follicle, to unravel the causes of ovary-based infertility and to consider novel ovary-selective approaches to contraception.
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PMID:Molecular control of ovulation and luteinization in the primate follicle. 1712


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