Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factors (IGFs) in adult mammalian plasma circulate predominantly in 150-kDa complexes that also contain IGF-binding protein-3 (IGFBP-3) and an acid-labile subunit. Proteolysis of IGFBP-3 within the 150-kDa complex decreases its affinity for IGFs, facilitating their release to the tissues. By contrast, 150-kDa complexes are not detected in serum from fetal or pregnant adult rats. Decreased complex formation results from insufficient availability of IGFBP-3 due to increased IGFBP-3 proteolysis. The present study characterizes IGFBP-3 protease activity in serum from fetal, pregnant and non-pregnant adult rats by comparing the effect of different protease inhibitors. Proteolysis of exogenous recombinant human IGFBP-3 (for fetal and pregnancy serum) or endogenous IGFBP-3 (for non-pregnant adult rat serum) following incubation at 37 degrees C was measured by ligand blotting. In all three sera, IGFBP-3 proteolysis was inhibited completely by: (i) EDTA, a chelator of divalent cations. Inhibition was reversed by zinc, but not by calcium ions; (ii) 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), an inhibitor of serine proteases; and (iii) a specific tissue inhibitor of matrix metalloproteinases (TIMP-1). Recombinant human matrix metalloproteinase-3 (MMP-3) proteolyzed recombinant human IGFBP-3 or endogenous rat IGFBP-3 in non-pregnancy serum pretreated with AEBSF to inactivate endogenous serine proteases. These results suggest that serine proteases initiate the activation of latent MMP precursor, and that the activated MMP directly degrades IGFBP-3.
...
PMID:Proteolysis of insulin-like growth factor binding protein-3 in serum from pregnant, non-pregnant and fetal rats by matrix metalloproteinases and serine proteases. 1022 1

The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has been shown to be involved in malignant tumor progression and therefore represents an attractive therapeutical target. In order to screen for ST3 synthetic inhibitors, we have produced and purified the catalytic domain of ST3, matrilysin, stromelysin-2, and membrane type-1 MMP from inclusion bodies in a bacterial system. Our strategy allowed the purification of MMPs directly in the active form, thereby avoiding in vitro activation. A total of 140,000 synthetic compounds from the Bristol-Myers Pharmaceutical Research Institute chemical deck were tested, using a substrate-based colorimetric enzymatic assay, in which ST3 activity was evaluated through its ability to cleave and inactivate alpha-1 proteinase inhibitor. One ST3 inhibitor belonging to the cephalosporin family of antibiotics was thereby identified.
...
PMID:Purification of active matrix metalloproteinase catalytic domains and its use for screening of specific stromelysin-3 inhibitors. 1033 63

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
...
PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32

Spontaneous resorption of herniated nucleus pulposus (HNP) is commonly observed when there is substantial contact of the disc with the spinal canal. We already demonstrated the expression of matrix metalloproteinase (MMP)-3 (stromelysin-1) in the granulation tissues of HNP, suggesting its role in the resorption process of HNP. Recent studies of osteoarthritic cartilages reported an up-regulated expression of metalloproteinases including MMP-7 (matrilysin) and MMP-8 (neutrophil collagenase), suggesting their roles in the matrix degradation. To clarify the expression of MMP-7 and MMP-8 in HNP, immunohistological analysis of various types of HNP was performed. We found MMP-7 was expressed in infiltrated mononuclear cells and chondrocytes, whereas MMP-8 was specifically expressed in chondrocytes. The positive rate for both MMP-7 and MMP-8 significantly increased when HNP was exposed to the epidural space (p < 0.01). Our data suggest that not only MMP-3 but also MMP-7 and MMP-8 may play a role in the resorption process of HNP.
...
PMID:Up-regulated expression of matrilysin and neutrophil collagenase in human herniated discs. 1038 79

Normal wounds can heal by secondary intention (epidermal migration to cover a denuded surface) or by approximation of the wound edges (e.g., suturing). In healing by secondary intention, epidermis-derived MMPs are important. Keratinocyte migration begins within 3-6 hr post injury, as basal cells detach from underlying basal lamina and encounter a dermal substratum rich in type I collagen. Cell contact with type I collagen in vitro stimulates collagenase-1 expression, which is mediated by the alpha 2 beta 1 integrin, the major keratinocyte collagen-binding receptor. Collagenase-1 activity alone is necessary and sufficient for keratinocyte migration over a collagen subsurface. Stromelysins-1 and -2 are also found in the epidermis of normal acute wounds. Stromelysin-2 co-localizes with collagenase-1 and may facilitate cell migration over non-collagenous matrices of the dermis. In contrast, stromelysin-1 is expressed by keratinocytes behind the migrating front and which remain on basal lamina, i.e., the proliferative cell population. Studies with stromelysin-1-deficient mice that suggest this MMP plays a role in keratinocyte detachment from underlying basement membrane to initiate cell migration. In chronic ulcers, MMP levels are markedly elevated, in contrast to their precise temporal and spatial expression in acute wounds. Both collagenase-1 and stromelysin-1 are found in fibroblasts underlying the nonhealing epithelium, and stromelysin-1 expression is especially prominent. Two key questions underlie the use of MMP inhibitors and wound healing: (1) will these agents impair normal reepithelialization in wounds that heal by secondary intention; and (2) can MMP inhibitors be effective therapy for chronic ulcers? The answer to neither is known. Batimastat and marimastat appear not to interfere with normal wound healing, but only in sutured surgical wounds, a situation in which MMP expression has practically no role. We also show the first example of an in vivo immune response, contact hypersensitivity, which is dependent upon MMP activity. Using gene-deficient mice, we demonstrate that stromylysin-1 (MMP-3) is required for sensitization, whereas gelatinase B (MMP-9) is required for timely resolution of the reaction to antigenic challenge.
...
PMID:Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity. 1041 17

The balance between production and activation of MMPs and their inhibition by TIMPs is a crucial aspect of cancer invasion and metastasis. On the basis of the concept that MMPs synthesized in tissues seep into the bloodstream, we have examined MMP levels in the plasma of patients with cancer. In colorectal, breast, prostate, and bladder cancer, most patients with aggressive disease have increased plasma levels of gelatinase B. In patients with advanced colorectal cancer, high levels of either gelatinase B or TIMP complex were associated with shortened survival. We propose that these assays may be clinically useful in characterizing metastatic potential in selected kinds of cancer. In rheumatoid arthritis and systemic lupus erythematosus (SLE), serum and plasma levels of stromelysin-1 were approximately 3-5-fold increased. Fluctuating serum stromelysin-1 levels in SLE did not correspond with change in disease activity. In SLE, stromelysin-1 may be a component of the chronic tissue repair process rather than being responsible for inciting tissue damage. On the basis of these observations, we conclude that measurement of plasma/serum MMP and TIMP levels may provide important data for selecting and following patients considered for treatment with drugs that interfere with MMP activity.
...
PMID:Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. 1041 33

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined. We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats. In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals. Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity. The mRNA expression pattern of six other MMPs was investigated. Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated. In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged. As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption. Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings. Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system.
...
PMID:Differential expression of matrix metalloproteinases in bacterial meningitis. 1043 Aug 40

Kaposi's sarcoma (KS) cells are considered to be of endothelial origin. KS lesions are characterized by hyperproliferation and an invasive phenotype. We have determined that KS cell cultures constitutively secrete multiple forms of several matrix metalloproteinases (MMPs) and an altered form of urokinase plasminogen activator (uPA) by zymogram and Western analysis of the culture media. MMPs are a family of secreted endoproteinases which degrade components of the extracellular matrix. Their enhanced expression and activity are strongly correlated with cellular processes involving tissue remodeling and invasion. The KS cells secrete increased levels of gelatinase A and B and a high molecular weight uPA in vitro when compared with non-KS endothelial or epithelial cells. Multiple forms of gelatinases A and B were observed on gelatin zymograms. Caseinolytic bands observed were confirmed by Western blot analysis to be due to stromelysin activity, whereas matrilysin was not detected by casein zymography. Western blot analysis also detected secretion of interstitial collagenase and high molecular weight uPA. Gelatinolytic activity with the mobility of gelatinase B was detected on gelatin zymograms, but not by Western analysis. This unusual constitutive expression pattern of MMPs and uPA by KS cells in vitro is characterized by elevated levels of gelatinase A, gelatinase B, interstitial collagenase, stromelysin and a high molecular weight form of uPA, and the lack of expression of matrilysin. These secreted MMPs, taken together, are capable of digesting a broad range of components of the extracellular matrix. This unusual pattern is likely to contribute to the characteristic hyperproliferative and invasive phenotype of KS lesions.
...
PMID:Expression of multiple matrix metalloproteinases and urokinase type plasminogen activator in cultured Kaposi sarcoma cells. 1044 93

The hypothesis of the present work was that the pannus tissue overlying the articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore analyzed the eventual presence of collagenase-3 and its regulation at the pannus-cartilage junction. Collagenase-3 mRNA (in situ hybridization) and enzyme protein (ABC and immunofluorescence staining) were found in the pannocytes in the pannus-hard tissue junction. Inflammatory round cells associated with the critical interface contained TNF-alpha and IL-1beta. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pannus-hard tissue junction. Active collagenase-3 was inhibited with alendronate (IC50 = 500-750 microM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated tissue destruction in rheumatoid arthritis.
...
PMID:Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate. 1051 87

This report describes the backbone amide dynamics of the uniformly 15N labeled catalytic domain of human stromelysin complexed to PNU-99533, a hydroxamate-containing ligand that binds to the S'1-S'3 region (right side) of the stromelysin active site, and to PNU-107859 and PNU-142372, both thiadiazole-containing ligands that bind to the S1-S3 region (left side) of the stromelysin active site. 15N R1, R2 and NOE NMR relaxation measurements were recorded and analyzed for each complex. Different dynamic behaviors were observed for stromelysin complexed to the two classes of ligands, indicating that it may be possible to use protein dynamics to distinguish between different binding orientations. In the absence of bound ligand at the S1-S3 subsites, the S1-S3 residues were found to be relatively rigid. In contrast, the S'1-S'3 subsites were found to be flexible in the absence of interactions with ligand. The relative rigidness of the S1-S3 subsites may be responsible for MMP binding specificity by discriminating between ligands of different shapes. By contrast, the inherent flexibility of the S'1-S'3 subsites allows structural rearrangement to accommodate a broad range of incoming substrates or inhibitors. Similarities and differences in dynamics observed for each complex provide insights into the interactions responsible for protein-ligand recognition. The relevance of protein dynamics to structure-based drug design is discussed.
...
PMID:Dynamics of stromelysin/inhibitor interactions studied by 15N NMR relaxation measurements: comparison of ligand binding to the S1-S3 and S'1-S'3 subsites. 1054 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---