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)

We have compared the effects of a general matrix metalloproteinase (MMP) inhibitor (CT435) with those of a concentration-dependent specific gelatinase inhibitor (CT543; Ki < 20 nM) on bone resorption in vitro. The test systems consisted of measuring: (i) the release of 45Ca2+ from prelabelled mouse calvarial explants; (ii) the release of 45Ca2+ from prelabelled osteoid-free calvarial explants co-cultured with purified chicken osteoclasts; and (iii) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. Both CT435 and CT543 dose-dependently inhibited the release of 45Ca2+ from neonatal calvarial bones stimulated by either parathyroid hormone or 1,25-dihydroxyvitamin D3. Moreover, CT543 produced a 40% inhibition at a concentration (10(-8) M) selective for the inhibition of human gelatinases A and B. CT435 (10(-5) M) and CT543 (10(-5) M) partially inhibited the release of 45Ca2+ from osteoid-free calvarial explants by chicken osteoclasts with a maximum of approximately 25% for unstimulated cultures, and approximately 36% for cultures stimulated by interleukin-1 alpha (IL-1 alpha; 10(-10) M). Neither inhibitor prevented lacunar resorption on ivory by unstimulated rat osteoclasts, but the compounds produced a partial reduction in both the number and total surface area of lacunae in IL-1 alpha-stimulated cultures, with maximal action at 10(-5) M. Neither of the inhibitors affected protein or DNA synthesis, nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme beta-glucuronidase. Immunocytochemistry demonstrated that isolated rabbit osteoclasts constitutively expressed gelatinase A and synthesized gelatinase B, collagenase and stromelysin, as well as the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) following IL-1 alpha stimulation. These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption. They further suggest that MMPs produced by osteoclasts are released into the sub-osteoclastic resorption zone where they participate in bone collagen degradation.
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PMID:The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts. 769 5

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.
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PMID:Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. 828 80

We report here that a 92-kD gelatinolytic metalloproteinase is expressed as protein and mRNA in human osteoarthritic cartilage, but not in normal adult articular cartilage. Western immunoblotting demonstrated that the 92-kD gelatinolytic activity corresponded to 92-kD type IV collagenase/gelatinase (gelatinase B); mRNA for gelatinase B was identified by Northern blotting. Chondrocytes from normal cartilage also exhibited mRNA for 72-kD type IV collagenase/gelatinase (gelatinase A), tissue collagenase, and stromelysin-1, and these mRNAs were increased in osteoarthritic cartilage. Regional analysis of osteoarthritic cartilage samples from four individuals revealed that gelatinase B mRNA was expressed in grossly fibrillated areas; two of four nonfibrillated cartilage samples failed to exhibit the mRNA, but did have increased levels of mRNA for other neutral metalloproteinases. IL-1 alpha treatment of normal human cartilage explants or isolated chondrocytes induced increased levels of gelatinase B and increased mRNA for tissue collagenase and stromelysin-1. Under identical conditions, mRNA levels for gelatinase A were not increased indicating that regulation of this enzyme in human articular chondrocytes is distinct from that of other metalloproteinases. Our data showing expression of gelatinase B in fibrillated cartilage suggest that it is a marker of progressive articular cartilage degradation in osteoarthritis.
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PMID:Expression of 92-kD type IV collagenase/gelatinase (gelatinase B) in osteoarthritic cartilage and its induction in normal human articular cartilage by interleukin 1. 832 82

Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell-derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-alpha and TGF-beta 1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-alpha mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-beta 1, TNF-alpha, and IL-1 alpha. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.
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PMID:Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of metalloproteinases-1. 897 86

Since the degradation of uterine cervical extracellular matrix is an essential process in cervical ripening and dilatation at term, we examined the effect of pregnancy on the level of pro-matrix metalloproteinase 9 (proMMP-9)/progelatinase B in the rabbit uterine cervix and its regulation in uterine cervical fibroblasts. Uterine cervices shortly before term parturition contained high levels of proMMP-9 compared with those of nonpregnant rabbits. Uterine cervical fibroblasts prepared from rabbits at 23 days of gestation did not produce proMMP-9; in contrast, interleukin (IL)-1 alpha, IL-1 beta, or phorbol 12-myristate 13-acetate (PMA) induced proMMP-9 production along with an increase of proMMP-9 mRNA, and the IL-1-mediated induction of proMMP-9 was synergistically enhanced by PMA. On the other hand, physiological concentrations of progesterone suppressed IL-1-and/or PMA-mediated production of proMMP-9 in a dose-dependent manner. This suppressive effect of progesterone on proMMP-9 production was accompanied by a decrease in matrix metalloproteinase 9 (MMP-9) mRNA, indicating that progesterone down-regulates the production of proMMP-9 at the transcriptional level. These results indicate that in the rabbit uterine cervix, IL-1 alpha and IL-1 beta are effective inducers of the proMMP-9 production, and progesterone is a physiological suppressor. Thus, MMP-9 and progesterone are very likely to play essential roles in cervical ripening and dilatation in the rabbit, and the production of MMP-9 in the cervix is finely regulated during pregnancy.
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PMID:Hormonal regulation of matrix metalloproteinase 9/gelatinase B gene expression in rabbit uterine cervical fibroblasts. 904 99

Matrix metalloproteinases (MMPs), among which is collagenase (MMP-1), are likely to be involved in various steps of the bone resorption process. As both production of these enzymes and bone resorption appear to be mediated by cytokines, we investigated the effects of two cytokines, IL-1 alpha and EGF, on the release of collagenase, gelatinase A (MMP-2), gelatinase B (MMP-9), TIMP-1 and calcium by rabbit calvariae. It was found that all these parameters increased under the influence of these cytokines. The release of calcium--used as a parameter of bone resorption--was highest in the combined presence of the cytokines. Although the absolute and relative enhancement by a combination of IL-1 alpha and EGF was most pronounced for collagenase (7-fold), both gelatinase A (5-fold) and gelatinase B (1.5-fold) had increased simultaneously. Calvariae produced a high level of MMP inhibitor (TIMP-1), especially under the influence of the cytokines; periosteum released little inhibitor. It is concluded that IL-1 alpha and EGF are likely to play a modulating role in the process of bone resorption.
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PMID:EGF and IL-1 alpha modulate the release of collagenase, gelatinase and TIMP-1 as well as the release of calcium by rabbit calvarial bone explants. 952 23

Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.
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PMID:Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. 975 50

Trachoma, a chronic follicular conjunctivitis caused by infection with Chlamydia trachomatis, is a leading cause of preventable blindness. The blinding complications are associated with progressive conjunctival scarring. Our immunohistochemical studies of conjunctival biopsies from children with active trachoma demonstrated the presence of both humoral and cell-mediated immune responses. Antichlamydial antibodies can neutralize Chlamydiae, block attachment and internalization of the organism, and can produce partial immunity. Our observations suggest a role for T-lymphocytes and cell mediated immunity in the genesis of conjunctival scarring. Conjunctival epithelial cells expressed major histocompatibility complex (MHC) class II antigens which might allow conjunctival epithelial cells to present Chlamydial antigens to T-cells enhancing the immune response. The epithelial cells expressing MHC class II antigens might present autoantigens to T-cells leading to induction of an autoimmune reaction. We have demonstrated that the conjunctival epithelial cells from patients with trachoma expressed interleukin (IL)-1 alpha and IL-1 beta. In addition, we have detected cytoplasmic expression of IL-1 alpha, IL-1 beta, tumor necrosis factor alpha and platelet-derived growth factor by macrophages. These cytokines have the potential to influence the remodeling and fibrosis observed in trachoma. Alterations of extracellular matrix components and collagen metabolism occur in the conjunctival tissue from patients with trachoma. New collagen type V formation was noted in active trachoma and scarred trachoma. The conjunctival tissue from patients with active trachoma contained increased amounts of collagen types I, III and IV. Scarred trachoma is characterized by marked increase in basement membrane--collagen IV and marked decrease in collagen types I and III. In addition, we demonstrated increased activity of gelatinase B and numbers of inflammatory cells containing gelatinase B in trachoma patients suggesting that this enzyme might be involved in matrix degradation and promotion of conjunctival scarring in trachoma.
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PMID:Immunology of trachomatous conjunctivitis. 1148 68