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)

Matrix metalloproteinases (MMPs, matrixins) are a family of zinc proteinases that digest extracellular matrix and play a very important role in normal development and pathological conditions such as cardiovascular diseases and cancer metastasis. Type IV collagenases (gelatinase A/MMP-2 and gelatinase B/MMP-9) may be critical in the early steps of angiogenesis, the digestion of basement membrane and the migration of endothelial cells from the existing blood vessels. Human dermal microvascular endothelial cells were cultured on type I collagen, type IV collagen, and reconstituted basement membrane Matrigel and differentiation was examined in the presence of potent synthetic inhibitors of MMPs. The thiol inhibitor MAG-283 had IC50 values of 480 nM and 3 nM against human interstitial collagenase (MMP-1) and MMP-2, respectively, and KI value of 2.2 nM against MMP-9. The sulfodiimine inhibitor YLL-224 had IC50 values of 180 nM, 63 nM, and 44 nM against MMP-1, -2, and -9, respectively. These inhibitors at very low micromolar concentrations inhibited cell-mediated type I collagen degradation and partially blocked cell invasion through type IV collagen. These inhibitors also suppressed endothelial differentiation, i.e., formation of capillary-like tubes on Matrigel and on type I collagen. These results suggest that collagen-degrading MMPs play an important role during the initiation of angiogenesis.
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PMID:Suppression of human microvascular endothelial cell invasion and morphogenesis with synthetic matrixin inhibitors. Targeting angiogenesis with MMP inhibitors. 1094 65

Fibroblast migration, proliferation, extracellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with pulmonary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamine and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF-induced lung fibroblast proliferation and chemotactic response in vitro. In addition, we examined the effect of heparin on both the induction of matrix metalloproteinases (MMPs) and MMPs activity in lung fibroblasts in vitro. Heparin, de-N-sulphated heparin but not heparan sulphate inhibited PDGF-induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF-stimulated human lung fibroblast chemotaxis. Negatively charged poly-L-glutamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant-proliferative and anti-chemotactic effects of heparin. Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPS, including MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). Only heparin inhibited both MMP-1 and MMP-2/MMP-9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP-1) and type 2 (TIMP-2) inhibited PDGF-stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity. The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF-induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.
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PMID:Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity. 1095 81

Chlamydia pneumoniae, an intracellular Gram-negative respiratory bacterium, and macrophages are present in inflammatory tissue sites such as atherosclerotic lesions, where abnormal degradation of the extracellular matrix takes place. To evaluate the potential of C pneumoniae for participation in matrix destruction, we studied the effect of this bacterium on the production of 3 matrix-degrading metalloproteinases, 92-kDa gelatinase, interstitial collagenase-1, and stromelysin-1, and their natural inhibitor TIMP-1 (tissue inhibitor of metalloproteinases-1) by human monocyte-derived macrophages differentiated in vitro. Spontaneous production of collagenase and stromelysin by these cells was minimal and was not influenced by C pneumoniae. In contrast, the cells secreted substantial basal quantities of 92-kDa gelatinase, the secretion of which was stimulated (on average, 2.5-fold) by C pneumoniae. C pneumoniae regulated the expression of 92-kDa gelatinase by macrophages at the pretranslational level. Macrophages secreted only small quantities of TIMP-1. The chlamydial proteins Omp2, MOMP, and HSP60 were also found to participate in the induction of 92-kDa gelatinase by C pneumoniae. Denaturation of chlamydial proteins by boiling reduced 92-kDa gelatinase secretion only partially (by 35%), suggesting that the heat-stabile lipopolysaccharide molecules also stimulate secretion of the enzyme. The results show that production of 92-kDa gelatinase by human macrophages is selectively upregulated by C pneumoniae, which suggests that these bacteria, when present in a macrophage-containing inflammatory environment, actively participate in the destruction of the extracellular matrix.
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PMID:Chlamydia pneumoniae proteins induce secretion of the 92-kDa gelatinase by human monocyte- derived macrophages. 1114 52

The family of matrix metalloproteinases (MMPs) comprises endopeptidases that are capable of degrading all extracellular matrix components. Given these actions, it is conceivable that MMPs may play a pathogenic role in inflammatory myopathies. These immune-mediated disorders are characterized by the invasion of mononuclear phagocytes and T lymphocytes and the loss of muscle fibres. We examined whether specific MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases; TIMPs) are expressed in muscle during acute inflammatory attacks by studying muscle biopsies obtained from patients diagnosed as having polymyositis, dermatomyositis, sporadic inclusion body myositis and, for comparison, from cases of various muscular dystrophies. Quantitative polymerase chain reaction analysis revealed significantly elevated mRNA expression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) in polymyositis and dermatomyositis and to a lesser extent in inclusion body myositis, whereas the level of expression of TIMPs remained unchanged in comparison with controls. Increased mRNA levels were associated with enhanced enzyme expression, as determined by immunoblotting, gelatin zymography and in situ zymography. Immunohistochemically, MMP-1 could be localized around the sarcolemma of diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed to be expressed primarily by invading T lymphocytes. Raised levels of MMPs could not be detected in the sera of affected patients, emphasizing the crucial action of MMPs in the inflamed muscle. Our results imply a pathogenic role for specific MMPs in the genesis of inflammatory myopathies, and open new strategies for therapeutic intervention.
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PMID:Expression of specific matrix metalloproteinases in inflammatory myopathies. 1115 61

The extracellular matrix metalloproteases (MMPs) secreted by various human tumor cells play a crucial role in tumor cell invasion and metastasis, but their expression in malignant mesothelioma (MM) cells has not been examined. In this study, we have investigated the spectrum of MMPs and tissue inhibitors of metalloproteases (TIMPs) produced by 8 MM cell lines. Using RT-PCR, we found that all investigated MM cell lines expressed genes encoding mRNA for MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-9 (gelatinase B) and TIMPs 1, 2 and 3. We also found that 6/8 MM cell lines expressed MMP-7 (matrilysin) and 3/8 MM cell lines expressed MMP-10 (stromelysin-2). MMP-11 (stromelysin-3) was not detected in any of the MM cell lines. Production of MMP-2 and MMP-9 was confirmed using gelatin zymography. In addition, all MM cell lines secreted a 66 kDa metalloprotease, while 3/8 MM cell lines secreted 46, 48, 51 and 63 kDa metalloproteases which specifically degraded the extracellular matrix components fibronectin, vitronectin and laminin. The 66 kDa protease was identified as MMP-3 by Western blot. Our results reveal a broad spectrum of MMPs and TIMPs produced by MM cells and indicate that different substrate specificities of MMPs may play a role in MM cell invasion.
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PMID:Expression and activity of matrix metalloproteases in human malignant mesothelioma cell lines. 1126 73

Prostate tissue was obtained from 22 radical prostatectomies (performed for clinical management of prostate carcinoma) immediately after surgery. A small piece of tissue was fixed immediately in formalin and used for routine histology while a second piece was frozen in OCT and used for immuno-histochemistry. Another small piece was used for isolation of epithelial and stromal cells. The remainder of the tissue was cut into 2 x 2 mm pieces and incubated in organ culture for 8 days. In organ culture, non-malignant, basal epithelial cells underwent a proliferative response. This was accompanied by de-differentiation of glandular structures and by migration of epithelial cells across the surface of the tissue. Erosion of the basement membrane could also be seen in places, but was not widespread. Invasion of epithelial cells into the adjacent stroma was not evident. Production of matrix metalloproteinases (MMPs) with gelatinolytic activity or collagenolytic activity was assessed in organ culture and compared to expression patterns in fresh tissue. MMP-1 (interstitial collagenase) and MMP-9 (92-kDa gelatinase B) were undetectable or low in fresh tissue specimens. Both enzymes were detected in organ culture and both increased over time. Even after 6 days, however, there was only a low level of gelatin-hydrolytic activity and no measurable collagen-hydrolytic activity. In past studies we used organ cultures of normal skin and malignant skin tumours (basal cell carcinomas) to help elucidate the role of collagenolytic and gelatinolytic MMPs in epithelial cell invasion (Varani et al, 2000). Compared to MMP levels observed in skin, levels of these enzymes in prostate are low. The low level of collagenolytic and gelatinolytic MMPs in fresh prostate tissue and in organ-cultured prostate tissue may help explain why there is little tissue destruction in many primary prostate tumours and why the majority of such tumours remain confined to the prostate for extended periods.
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PMID:Matrix metalloproteinases (MMPs) in fresh human prostate tumour tissue and organ-cultured prostate tissue: levels of collagenolytic and gelatinolytic MMPs are low, variable and different in fresh tissue versus organ-cultured tissue. 1130 57

A major function of alpha-1-antitrypsin (AAT) is the inhibition of overexpressed serine proteinases during inflammation. However, it is also known that the biological activity of AAT is affected by chemical modifications, including oxidation of the reactive-site methionine, polymerization, and cleavage by unspecific proteases, all of which will result in AAT inactivation and/or degradation. All inactive forms of AAT can be detected in tissues and fluids recovered from inflammatory sites. To test for a possible link between the inflammation-generated, noninhibitory, cleaved form of AAT and cellular processes associated with inflammation, we studied the effects of this form at varying concentrations on human monocytes in culture. We found that cleaved AAT at concentrations ranging between 1 and 10 microM in monocyte cultures over 24 h induces elevation in monocyte chemoattractant protein-1 (MCP-1) and pro-inflammatory cytokines such as TNFalpha and IL-6 and also increases production of interstitial collagenase (MMP-1) and gelatinase B (MMP-9), members of two different classes of matrix metalloproteinase. Moreover, monocytes stimulated with higher doses of cleaved AAT show an increase in cellular oxygen consumption by about 30%, while native AAT under the same experimental conditions inhibits oxygen consumption by about 50%. These results indicate that the cleaved form of AAT may play a role in monocyte recruitment and pro-inflammatory activation during inflammatory processes, and also suggest that changes in structure occurring upon AAT cleavage could alter its functional properties with potential pathological consequences.
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PMID:Effects of noninhibitory alpha-1-antitrypsin on primary human monocyte activation in vitro. 1136 45

Matrix metalloproteinases (MMPs) degrade extracellular proteins during epithelialization of wounds. To evaluate the biological significance of MMPs in epidermal healing, the synthetic broad-spectrum MMP inhibitor GM 6001 (also called Galardin and Ilomastat) was applied topically to standardized human wounds. GM 6001 (10 microg/microl) or vehicle alone was applied every second day onto 4 de-roofed 6 mm suction blister wounds on the volar forearm of healthy male volunteers for 12 days. GM 6001 delayed healing by 2-4 days as assessed macroscopically and microscopically. In situ hybridization or immunohistochemistry showed that MMP-1 (interstitial collagenase) was present in and MMP-2 (gelatinase A) close to laterally migrating keratinocytes whereas MMP-9 (gelatinase B) was seen during maturation of new epidermis. MMP-1 was undetectable in blister roofs (normal epidermis) and found in low levels in normal skin. Total MMP-1 activities increased about 100-fold in wounds, independent of treatment, compared to normal skin as analyzed by specific ELISA-based activity assay. By gelatin zymography, MMP-2, but not MMP-9, was detected in blister roofs and wound healing was associated with increased active MMP-2 and latent MMP-9 levels. GM 6001 prevented activation of MMP-2 and increased latent MMP-9 levels. GM 6001 delayed re-appearance of laminin-5, the synthesis of which correlated with epidermal regeneration. Restoration of stratum corneum, measured indirectly by transepidermal water loss, was also impaired (P<0.05) in the GM 6001 group. In conclusion, pharmacological MMP inhibition delayed epidermal regeneration in vivo, suggesting that MMPs are required to restore epidermis after epidermal ablation in humans.
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PMID:Topical synthetic inhibitor of matrix metalloproteinases delays epidermal regeneration of human wounds. 1158 31

Organ cultures of human skin were incubated for 8 days under growth factor-free conditions or exposed to 10 ng ml(-1) of human recombinant epidermal growth factor (EGF) during the incubation period. Normal histological features were preserved in the absence of growth factor, while epithelial cells underwent a proliferative response and invaded the underlying stroma in the presence of exogenous EGF. The same concentrations of EGF that induced stromal invasion also resulted in up-regulation of matrix metalloproteinase-9 (MMP-9; 92-kD gelatinase B) in organ culture and keratinocyte monolayer culture, and expression of MMP-1 (interstitial collagenase) in organ culture and fibroblast monolayer culture. When skin organ cultures were exposed to a potent, irreversible EGF-receptor tyrosine kinase (EGF-RTK) antagonist along with EGF, abnormal histological features were reversed, and MMP-9 production was suppressed. In contrast, EGF-RKT antagonism had only a modest inhibitory effect on MMP-1 production. Culture fluid from keratinocytes grown in monolayer culture stimulated fibroblast proliferation and MMP-1 elaboration. Treatment of fibroblasts with the same EGF-RTK antagonist inhibited keratinocyte-induced fibroblast proliferation but had only a modest inhibitory effect (approximately 20% inhibition) on MMP-1 production. In contrast, treatment of dermal fibroblasts with Interleukin-1 Receptor Antagonist had no effect on keratinocyte-induced fibroblast growth but strongly inhibited MMP-1 production (greater than 70% inhibition). These data indicate that stromal invasion by epithelial cells in EGF-treated skin is associated with events occurring in both the epidermis and dermis. The direct effect of the exogenous growth factor appears to be primarily on the epidermis. Dermal events reflect, at least in part, a response to factors elaborated in the epidermis.
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PMID:Induction of matrix metalloproteinase-1 (MMP-1) during epidermal invasion of the stroma in human skin organ culture: keratinocyte stimulation of fibroblast MMP-1 production. 1172 Apr 51

We investigated the role of polymorphonuclear neutrophil (PMN) proteinases, elastase, and gelatinase B in rat models of acute lung injury. Three groups of rats were studied 6 hours after unilateral instillation of hydrochloric acid (HCl; 0.1 N), lipopolysaccharide (LPS) (4 microg), or saline. The results demonstrated that HCl-induced lung injury, as compared with LPS-induced lung injury, was associated with an increase in permeability (wet/dry weight ratio and proteins in bronchoalveolar lavage fluid). In contrast, there was similar PMN recruitment (in bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenates) and similar proteinase exocytosis (residual alveolar PMN content of elastase and gelatinase B) in both types of lung injury. In situ zymography, evaluating interstitial protease/inhibitor balance, demonstrated a decrease in gelatinolytic activity in both HCl- and LPS-injured lungs compared with normal lung. The increase in interleukin 6 concentration in lung homogenates, which is observed after both injuries compared with saline-instilled animals, could be involved in up-regulation of tissue inhibitor of matrix metalloproteinase-1, shown by immunocytochemistry to participate in antiproteinase excess. Neither inhibition of alveolar neutrophil influx using a leukocyte elastase inhibitor (EPI-hNE-4) nor inhibition of gelatinase activities by recombinant adenovirus for the human tissue inhibitor of matrix metalloproteinase 1 gene transfer decreased lung edema in HCl-induced injury. These data suggest that PMN proteinases do not contribute to HCl-induced acute lung injury in rats.
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PMID:Neutrophil proteinases in hydrochloric acid- and endotoxin-induced acute lung injury: evaluation of interstitial protease activity by in situ zymography. 1185 May 27


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