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)

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.
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PMID:Matrix metalloproteinases and processing of pro-TNF-alpha. 775 57

Pneumocystis carinii pneumonia (PCP) is characterized by the formation of leaky alveoli and a foamy alveolar exudate. To induce PCP, male Wistar rats were immunosuppressed by oral dexamethasone treatment for 12 weeks, during which time all rats developed PCP. Bronchoalveolar lavage fluid (BALF) was analyzed at that time and at 1, 2, and 4 weeks after the cessation of dexamethasone treatment, during which time the rats were recovering from PCP and immunosuppression (and was compared with the BALF obtained from healthy control rats), for type IV collagenase, elastase, cathepsin G, and collagenase activities. Scores for 72-kDa (matrix metalloproteinase type [MMP-2]) and 92-kDa (MMP-9) type IV collagenase-gelatinase activities correlated with those for BALF macrophages (r = 0.58; P < 0.001) and neutrophils (r = 0.66; P < 0.001), respectively, suggesting that they may, in part, be derived from these cells. However, MMP-2 was constitutively expressed and may play a role in normal tissue remodeling. MMP-9 activity was highest in the group with PCP (1.8 +/- 0.37; P > 0.05), with a gradual decline (1.0 +/- 0.48 by week 4; P > 0.05) toward normal (0.67 +/- 0.42) during recovery, which suggests a role for it in tissue-destructive inflammatory events. In rats with PCP the endogenously active collagenase was present at high levels compared with those in healthy controls (2.6 +/- 0.69 versus 0.17 +/- 0.17, respectively; P < 0.01), but they returned to normal by week 4 of recovery (0.42 +/- 0.30; P > 0.05). Collagenase activity showed a correlation with cyst number (r = 0.57; P < 0.001). The BALF of rats with PCP also contained the serine proteinases, which may act as pro-MMP activators. Ultramorphology disclosed increased pinocytotic activities, subepithelial bleb formation, and degeneration and denudation of the basal lamina. These findings suggest that the increased activities of collagenases in BALF caused by the host response against P. carinii might contribute to leaky alveoli.
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PMID:Collagenases and the serine proteinases elastase and cathepsin G in steroid-induced Pneumocystis carinii pneumonia. 779 Apr 46

Matrix metalloproteinase 7 (MMP-7) has been purified as an inactive zymogen of M(r) 28,000 (proMMP-7) from the culture medium of CaR-1 human rectal carcinoma cells. The NH2-terminal sequence of proMMP-7 is Lys-Pro-Lys-Pro-Gln-Glu, which is identical to that of matrilysin. The zymogen is activated by 4-aminophenylmercuric acetate (APMA), yielding an intermediate form of M(r) 21,000 and an active species of M(r) 19,000 which shows the new NH2-terminal sequence of Tyr78-Ser-Leu-Phe-Pro-Asn-Ser. Although trypsin fully activates the zymogen, the activation rate by plasmin or leukocyte elastase is confined to approximately 50%. ProMMP-7 can be activated by MMP-3 (stromelysin 1) to its full activity in a single-step mechanism and generates the same NH2 terminus obtained by APMA activation, whereas MMP-1 (tissue collagenase), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) do not have such an effect. On the other hand, proMMP-1 is activated by MMP-7 to an activity similar to that obtained by APMA and the activation by MMP-7 is enhanced up to approximately 6.5 fold in the presence of APMA. This enhanced activity is donated by specific cleavage at the Gln80-Phe81 bond of proMMP-1. MMP-7 can also activate proMMP-9 up to approximately 50% of the full activity with a new NH2 terminus of Leu16-Arg-Thr-(Asn)-Leu. Incubation of proMMP-2 or proMMP-3 with MMP-7 results in no activation of these proMMPs. MMP-7 degrades type IV collagen, laminin-1, fibronectin, proteoglycan, type I gelatin, and insoluble elastin. These results suggest that in vivo MMP-7 may play a role in degradation of extracellular matrix macromolecules in concert with MMP-1, -3, and -9 under pathological conditions.
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PMID:Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. 789 11

Myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). In renovascular hypertension, this presents as a reactive perivascular and interstitial fibrosis in not only the pressure overloaded, hypertrophied left ventricle but also the normotensive, nonhypertrophied right ventricle. It therefore would appear that circulating hormonal and not hemodynamic factors are responsible for this adverse fibrous tissue response. To ascertain whether the RAAS effector hormones angiotensin II (AII) or aldosterone (ALDO) directly stimulate collagen synthesis or inhibit collagenase production we used cell culture. Adult rat cardiac fibroblasts (Fb) were cultured since these cells express mRNA for types I and III collagens, the major fibrillar collagens in the heart, and collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Collagen synthesis, determined by 3H-proline incorporation, and collagenase activity were measured in confluent, quiescent Fb after 24 h incubation with various concentrations of AII or ALDO (10(-11)-10(-6)M) in the presence or absence of either 10(-5)M type 1 (DuP 753) and type 2 (PD 123177) AII or 10(-9)-3 x 10(-6)M ALDO (spironolactone) receptor antagonists, respectively. Collagen synthesis, normalized per total protein synthesis, increased significantly (P < 0.005) after incubation with either 10(-9)M ALDO (5.9 +/- 1.0%) or 10(-7)M AII (5.3 +/- 1.2%) compared with untreated control cells (2.9 +/- 0.5%) of the same passage (p6-p10). This increase in collagen synthesis could be completely abolished by either types 1 or 2 AII receptor antagonists in AII stimulated Fb or the competitive ALDO receptor antagonist, spironolactone, at equimolar concentration in ALDO stimulated Fb. AII significantly decreased collagenase activity which could be completely abolished by PD 123177, but not DuP 753, while ALDO had no effect on collagenase activity. The mineralocorticoid, ALDO, stimulates collagen synthesis in cultured adult rat cardiac Fb in concentrations similar to those found in plasma in renovascular hypertension and this response appears to occur via type I corticoid receptors. AII appears to stimulate collagen synthesis by both type 1 and 2 AII receptors, but only in high concentrations that could be generated locally within the myocardium. In addition, AII unlike ALDO inhibits collagenase activity that could be attenuated only by type 2 receptor blockade. These findings suggest a direct interaction between ALDO, AII and cardiac Fb in mediating myocardial fibrosis in hypertensive heart disease.
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PMID:Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. 796 49

alpha 1-antitrypsin, the primary physiologic inhibitor of human leukocyte elastase, is proteolytically inactivated by several matrix metalloproteinases including interstitial collagenase, stromelysin and 92 kDa gelatinase. In this report, we describe the catalytic effects of matrilysin, a recently identified metalloproteinase, upon alpha 1-antitrypsin. Matrilysin was found to be approximately 30-fold more effective than 92kDa gelatinase, 70-fold more effective than collagenase, and 180-fold more effective than stromelysin. Cleavage of alpha 1-antitrypsin by matrilysin produced two fragments of approximately 50 kDa and 4 kDa. The single cleavage occurred at the Phe352-Leu353 peptide bond, a locus within alpha 1-antitrypsin's active-site loop. These results suggest that apart from its activity against extracellular matrix, matrilysin provides a mechanism for the regulation of leukocyte elastase activity through its capacity to degrade alpha 1-AT.
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PMID:Matrilysin is much more efficient than other matrix metalloproteinases in the proteolytic inactivation of alpha 1-antitrypsin. 798 May 22

A galactose-binding protein of M(r) = 30,000 previously described in baby hamster kidney cells (Foddy, L., Stamatoglou, S. C., and Hughes, R. C. (1990) J. Cell Sci. 97, 139-148) has been analyzed by the cloning and sequencing of cDNA clones encoding the complete sequence and an amino-terminal fragment. The intact lectin CBP30 contains 245 amino acid residues, including the initiating methionine residue, and is closely homologous to mammalian S-type lectins of similar size characterized in human, rat, and mouse species. The carboxyl-terminal domain contains the carbohydrate binding activity and the amino-terminal domain, which is extremely sensitive to bacterial collagenase, contains a repetitive sequence rich in glycine, tyrosine, and proline. There are 8 repeats in hamster CBP30, as in the human homologue, compared with about 10 in rat and mouse and > 10 in dog homologues. This repeat sequence is also sensitive to the tissue metalloproteinases, gelatinase B and matrilysin, but, unlike the bacterial collagenase, the mammalian enzymes also cause extensive degradation of the carbohydrate binding carboxyl domain. Physical measurements using CD and tryptophan fluorescence spectroscopy indicate that the two domains of CBP30 are structurally, as well as functionally, distinct and independent. Cross-linking studies indicate that the amino-terminal lectin fragment can efficiently self-assemble into oligomeric species, and less efficient but significant aggregation of the intact lectin is also shown. Domain-specific antibodies to hamster CBP30 have been prepared and used to show that only the full-length, undegraded form of CBP30 is present in whole cell lysates.
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PMID:Structure of baby hamster kidney carbohydrate-binding protein CBP30, an S-type animal lectin. 802 86

We have explored the tissue localization of extracellular matrix metalloproteinases MMP-1 (fibroblast collagenase), MMP-2 (72-kDa gelatinase/Type IV collagenase), MMP-3 (stromelysin), MMP-8 (polymorphonuclear leukocyte collagenase) and MMP-9 (92-kDa gelatinase/Type IV collagenase) in the tissues around loose hip prostheses. The findings were compared with those in synovial tissues obtained from patients with a fractured femoral neck. MMP-type specific antisera were applied in the sensitive avidin-biotin-peroxidase complex methods. MMP-1 was found in monocyte/macrophages, fibroblasts, and vascular endothelial cells in both interface tissues between bone and acetabular components and the pseudocapsular tissues obtained from loosening of hip prostheses. In these tissues, MMP-8 was occasionally found, but only in polymorphonuclear leukocytes. Cells showing immunoreactivity to 72- and 92-kDa gelatinase/Type IV collagenase, MMP-2 and MMP-9, respectively, and stromelysin, MMP-3, were abundant in both interface and pseudocapsular tissues in loose hip prostheses. In contrast, in hip fractures, immunoreactivity to MMP-1, 2, 3, and 9 was weak and only observed in synovial tissues. Immunoreactivity to MMP-8 was confined to polymorphonuclear leukocytes attached to the synovial membrane or in the infiltrate around blood vessels in the subsynovial connective tissues. The finding of MMP-1, 2, 3, and 9 in the tissues around loose hip prostheses suggests that they play a role in the weakening of connective tissues, and this leads to loosening.
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PMID:Extracellular matrix metalloproteinases around loose total hip prostheses. 804 79

In this study, we have used high resolution gel-filtration chromatography and measurements of Ki to compare the capacity of full-length native stromelysin, C-terminal truncated stromelysin (Phe100-Pro273), and matrilysin (the only metalloproteinase spontaneously lacking a C-terminal hemopexin-like domain) to bind to the tissue inhibitor of metalloproteinases (TIMP). While prostromelysin failed to bind TIMP, active stromelysin bound to the inhibitor avidly, exhibiting an affinity for TIMP (Ki = 8.3 x 10(-10) M) essentially identical to that of active interstitial collagenase as determined by competition experiments. C-terminal truncated stromelysin also formed a higher M(r) complex with TIMP which survived gel filtration. However, when truncated stromelysin was forced to compete with its full-length parent molecule for limiting amounts of TIMP, the full-length enzyme preferentially bound to the inhibitor. Indeed, binding studies indicated a Ki of 5.95 x 10(-9) M for the truncated variant's interaction with TIMP, only 14% as tight as that of full-length stromelysin. We also examined the interaction between TIMP and matrilysin, the only metalloproteinase which naturally lacks a C-terminal domain. Promatrilysin failed to bind the inhibitor. However, active matrilysin readily bound TIMP, forming a complex that resisted separation by gel filtration. When active matrilysin was forced to compete with truncated stromelysin for limiting amounts of TIMP, both enzymes appeared to complex the inhibitor with nearly equivalent efficacy. Indeed, active matrilysin exhibited a Ki for TIMP of 4.5 x 10(-9) M, essentially identical to that of truncated stromelysin. These data indicate that, as is true for collagenase, the C-terminal domain of stromelysin contributes significantly to its capacity to bind the physiologic inhibitor, TIMP. Furthermore, since stromelysin readily processes in vitro to a C-terminal truncated form, this enzyme species, as well as the full-length metalloproteinase matrilysin, may resist inhibition by TIMP in areas of active inflammation in vivo.
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PMID:Contribution of the C-terminal domain of metalloproteinases to binding by tissue inhibitor of metalloproteinases. C-terminal truncated stromelysin and matrilysin exhibit equally compromised binding affinities as compared to full-length stromelysin. 817 79

The actions of recombinant human fibroblast collagenase (MMP1), purified polymorphonuclear leucocyte collagenase (MMP8) and their N-terminal catalytic domain fragments against cartilage aggrecan and an aggrecan G1-G2 fragment have been investigated in vitro. After activation with recombinant human stromelysin and typsin, both collagenases were able to degrade human and porcine aggrecans to a similar extent. An N-terminal G1-G2 fragment (150 kDa) was used to identify specific cleavage sites occurring within the proteinase-sensitive interglobular domain between G1 and G2. Two specific sites were found; one at an Asn341-Phe342 bond and another at Asp441-Leu442 (human sequence). This specificity of the collagenases for aggrecan G1-G2 was identical with that of the truncated metalloproteinase matrilysin (MMP7), but different from those of stromelysin (MMP3) and the gelatinases (MMP2 or gelatinase A; MMP9 or gelatinase B) which cleave at the Asn-Phe site, but not the Asp-Leu site. In addition, collagenase catalytic fragments lacking C-terminal hemopexin-like domains were tested and shown to exhibit the same specificities for the G1-G2 fragment as the full-length enzymes. Thus the specificity of the collagenases for cartilage aggrecan was not influenced by the presence or absence of the C-terminal domain. Together with our previous findings, the results show that stromelysin-1, matrilysin, gelatinases A and B and fibroblast and neutrophil collagenases cleave at a common, preferred site in the aggrecan interglobular domain, and additionally that both fibroblast and neutrophil collagenases cleave at a second site in the interglobular domain that is not available to stromelysin or gelatinases.
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PMID:Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain. 821 28

We reported that interstitial collagenase is produced by keratinocytes at the edge of ulcers in pyogenic granuloma, and in this report, we assessed if production of this metalloproteinase is a common feature of the epidermal response in a variety of wounds. In all samples of chronic ulcers, regardless of etiology, and in incision wounds, collagenase mRNA, localized by in situ hybridization, was prominently expressed by basal keratinocytes bordering the sites of active re-epithelialization indicating that collagenolytic activity is a characteristic response of the epidermis to wounding. No expression of mRNAs for 72- and 92-kD gelatinases or matrilysin was seen in keratinocytes, and no signal for any metalloproteinase was detected in normal epidermis. Immunostaining for type IV collagen showed that collagenase-positive keratinocytes were not in contact with an intact basement membrane and, unlike normal keratinocytes, expressed alpha 5 beta 1 receptors. These observations suggest that cell-matrix interactions influence collagenase expression by epidermal cells. Indeed, as determined by ELISA, primary cultures of human keratinocytes grown on basement membrane proteins (Matrigel; Collaborative Research Inc., Bedford, MA) did not express significant levels of collagenase, whereas cells grown on type I collagen produced markedly increased levels. These results suggest that migrating keratinocytes actively involved in re-epithelialization acquire a collagenolytic phenotype upon contact with the dermal matrix.
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PMID:Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. 825 40


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