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

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glomerular and other vascular basement membranes were found to contain an antigen that was immunochemically indistinguishable from serum amyloid P-component. There was no immunological cross-reactivity between antisera to serum amyloid P-component and to collagen types I, III, IV, or V. The amyloid P-component antigen was confined to the endothelial aspect, the lamina rara interna, of glomerular basement membrane. It could not be eluted by high-ionic-strength saline, EDTA, dithiothreitol, or either polar or nonpolar detergents, but was released into solution when isolated glomerular basement membrane was digested by highly purified bacterial collagenase. Most of these P-component molecules and their constituent polypeptide chains were of higher molecular weight and lower isoelectric point than serum amyloid P-component. These findings indicate that, as well as being a normal plasma protein and a universal constituent of amyloid deposits, P-component is also a normal matrix glycoprotein of basement membrane in which it is covalently linked to collagen and/or other matrix proteins. This may be relevant both to the pathogenesis of amyloidosis and to other aspects of physiology and pathology of basement membranes.
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PMID:Amyloid P-component is a constituent of normal human glomerular basement membrane. 700 Sep 64

Amyloidosis was induced in mice by the simultaneous injection of sodium caseinate and heat-killed M. butyricum. Amyloid fibrils were isolated by collagenase digestion, 1 M NaCl extraction and repeated washing with 0.15 M NaCl. The amyloid fibril fraction was practically free of contaminations such as collagen, chromatin and membranes as judged by electron microscopic morphometry. The protein AA was purified from the isolated fibrils to an apparent homogeneity as judged by sodium dodecyl sulphate polyacrylamide gel electrophoresis using one step gel filtration from Sephacryl S-200 in the presence of 6 M guanidine-HCl and 50 mM dithiothreitol. The molecular weight of the peptides of the protein AA were 8,500 and 10,000.
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PMID:Purification of amyloid fibrils and protein AA from mouse amyloid deposits induced by caseinate and M. butyricum. 723 20

beta 2-Microglobulin (beta 2M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a complication of long-term hemodialysis. However, the pathological role of beta 2M in HAA remains to be determined. Recently, we demonstrated that beta 2M in the amyloid deposits of HAA is modified with advanced glycation end products (AGEs) of the Maillard reaction. Since AGEs have been implicated in tissue damage associated with diabetic complications and aging, we investigated the possible involvement of AGE-modified beta 2M (AGE-beta 2M) in the pathogenesis of HAA. AGE- and normal-beta 2M were purified from urine of long-term hemodialysis patients. AGE-beta 2M enhanced directed migration (chemotaxis) and random cell migration (chemokinesis) of human monocytes in a dose-dependent manner. However, normal-beta 2M did not enhance any migratory activity. AGE-beta 2M, but not normal-beta 2M, increased the secretion of TNF-alpha and IL-1 beta from macrophages. Similar effects were also induced by in vitro prepared AGE-beta 2M (normal-beta 2M incubated with glucose in vitro for 30 d). When TNF-alpha or IL-1 beta was added to cultured human synovial cells in an amount equivalent to that secreted from macrophages in the presence of AGE-beta 2M, a significant increase in the synthesis of collagenase and morphological changes in cell shape were observed. These findings suggested that AGE-beta 2M, a major component in amyloid deposits, participates in the pathogenesis of HAA as foci where monocyte/macrophage accumulate and initiate an inflammatory response that leads to bone/joint destruction.
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PMID:Involvement of beta 2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-alpha and interleukin-1. 811 90

Immunolocalization of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in periarticular tissues of beta 2-microglobulin amyloidosis patients was investigated. MMP-1 (interstitial collagenase) the most strongly expressed of the MMPs, was localized in the synovial lining cells, mesenchymal cells in granulation tissue and nodular amyloid deposits, and chondrocytes within areas of cartilage erosion. Expression of MMP-1 was correlated with the degree of macrophage infiltration and synovial cell hyperplasia, but it was not correlated with the degree of amyloid deposition or haemodialysis period. Expression of MMP-1 appeared more intense than that of TIMP-1 and TIMP-2 in highly inflammatory cases. MMP-2 was mildly expressed in the interstitial fibroblasts and MMP-3 was faintly stained in the extracellular matrix of the synovial membrane. MMP-9 (gelatinase B) was found to be strongly positive in the osteoclasts which increased in the progressing osteolytic lesion from the destructive arthropathy. These results suggest involvement of MMPs in inflammation with an imbalance between expression of MMPs and TIMPs being closely related to pathogenesis of the destructive arthropathy.
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PMID:Increased matrix metalloproteinases as possible cause of osseoarticular tissue destruction in long-term haemodialysis and beta 2-microglobulin amyloidosis. 864 67

beta 2-Microglobulin (beta 2-m) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a serious complication in patients on long-term hemodialysis. The most distinctive pathological feature of HAA is the deposition of amyloid fibrils with subsequent articular inflammation and destruction. However, the pathological role of beta 2-m is not well known at present. We investigated the effects of beta 2-m on the production of proteinases from synovial fibroblasts isolated from patients with rheumatoid arthritis. beta 2-m stimulated synovial fibroblasts to produce stromelysin, a neutral matrix metalloproteinase (MMP-3). The production of MMP-2 and of a tissue inhibitor of metalloproteinase-1 (TIMP-1) were not enhanced by beta 2-m-treated synovial fibroblasts. Stromelysin is capable of degrading several components of the extracellular matrix and believed to be the key enzyme causing articular destruction in inflammatory joint diseases. Our results suggest a novel role for beta 2-m in articular inflammation and destruction mediated by stromelysin in HAA.
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PMID:Beta 2-microglobulin induces stromelysin production by human synovial fibroblasts. 934 81

Light (L) chain dimers expressed by multiple myeloma cells and collected as Bence-Jones proteins from the urine of human subjects were tested for their ability to form deposits in fibroblast monolayer cell cultures. Bence-Jones proteins from subjects with primary amyloidosis associated with L chains were shown to form fibrillar deposits by the in vitro assay introduced in this report. Filaments interspersed with nascent collagen could be detected after only 48 h. Deposition of L chains continued over a period of 72 h culminating in the appearance of dense fibrils with widths of 80-100 A and a variety of lengths. Formation of amyloid-like fibrils was accompanied by interference with the maturation of the collagen produced by the fibroblast cells. Fibrils composed of the Mcg lambda-type L chain were deposited between collagen fibers, thus expanding them laterally and leading to their partial disintegration. Mature collagen was completely missing from fibroblast monolayers exposed to the Sea lambda chain and the Jen kappa chain. Collagen with the characteristic striped pattern matured normally in control samples, such as those not dosed with amyloid precursors or those treated with a non-amyloidogenic Bence-Jones protein (e.g., the Hud lambda chain dimer). By immunochemical techniques using fluorescein- and gold-labeled anti-L chain antibodies, amyloidogenic L chains were shown to decorate the strands of nascent collagen. This observation suggests that amyloidogenic L chains are concentrated in the extracellular matrix by monovalent antigen-antibody type reactions. The capacity of the Mcg L chain dimer to bind collagen-derived sequences was tested by soaking crystals with a collagenase substrate, PZ-Pro-Leu-Gly-Pro-D-Arg. Difference Fourier analysis at 2.7 A resolution indicated that the PZ-peptide is a site-filling ligand. It could not be removed from the active site by perfusion of the crystal with ammonium sulfate crystallizing media. Similar experiments with the collagen-derived peptide (Pro-Pro-Gly)(5) showed substantial hysteresis effects extending from one end of the Mcg dimer to the other. After the ligand was withdrawn, the active site of the Mcg dimer could no longer bind the PZ-peptide. However, if the active site was first blocked by the PZ-peptide and subsequently exposed to the (Pro-Pro-Gly)(5) peptide, the difference Fourier map was indistinguishable from that obtained with the PZ-peptide alone. We concluded that amyloidogenic L chains such as the Mcg dimer could be concentrated in the perivascular space by binding to normal tissue constituents. These components include nascent collagen, which can be deterred from maturing as a result of this binding. Participation in such pathological activity is also self-destructive to the amyloidogenic L chains, which lose their binding capabilities for collagen-derived peptides and also become susceptible to irreversible conversion to amyloid fibrils. All of these events may be prevented by prior treatment of the amyloidogenic L chains with site-filling ligands. (c) 2000 John Wiley & Sons, Ltd.
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PMID:Binding of nascent collagen by amyloidogenic light chains and amyloid fibrillogenesis in monolayers of human fibrocytes. 1093 57

Hemodialysis-related amyloidosis is a relatively new form of systemic amyloidosis, with beta2-microglobulin (B2M) being identified as the major constituent protein. Most of the clinical findings are related to amyloid deposition in osseo-articular tissues. B2M amyloid deposits first appear in the cervical intervertebral discs, which are well known to be susceptible to mechanical stress. A close relationship between changes of microenvironment caused by such stress and amyloid deposition is highly suggested. In advanced cases, an inflammatory reaction composed of macrophages, multinucleated giant cells, and granulation tissue, is observed around the amyloid deposits. Purified amyloid protein is native B2M, and mutations and proteolysis are not believed to be important for its deposition. Plasma levels of B2M are elevated as much as 5-10 times because of the inability of hemodialysis equipment removal of B2M from blood plasma, the duration being very important for B2M amyloid fibrillogenesis. Heparan sulfate proteoglycans, perlecan, is increased at the same sites of amyloid deposits from the early stages. In B2M amyloidosis, an increase of heparan sulfate proteoglycans is observed in the vascular wall and synovium, but in the discs, ligaments and cartilage, there is an increase of chondroitin sulfate proteoglycans predominantly. B2M has an affinity for heparan sulfate proteoglycans, although it is weaker than that for laminin and type IV collagen. This is related to the interactions between negative charges of sulfate groups of proteoglycans and positive charges of basic amino acids in N-terminal side of B2M. Increased cytokines production in the synovium, induced by advanced glycation end products as well as elevated plasma levels, is also linked to inflammatory reactions. Increased expression of matrix metalloproteinases (MMP), especially MMP-1 and -9, is related to the destructive changes of the bone and cartilage. The decrease of plasma levels by high flux membrane and control of inflammatory reactions are very important for prevention of B2M amyloidosis.
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PMID:Pathogenesis of beta2-microglobulin amyloidosis. 1114 56

Beta-2 microglobulin (beta 2M, molecular weight 10,000) is a 99 residue immune system protein which is part of the MHC Class I complex whose role is to present antigens to T cells. beta 2M serum levels rise dramatically in renal failure, and a syndrome called "dialysis associated amyloidosis" occurs with time in a majority of hemodialysis patients who exhibit beta 2M amyloid deposits in joints, bone and other organs. beta 2M can also induce Ca++ efflux from calvariae, collagenase production, and bone resorption. We report here that beta 2M formed relatively nonselective, long-lived, voltage independent ion channels in planar phospholipid bilayer membranes at physiologically relevant concentrations. The channels were inhibited by Congo red and blocked by zinc suggesting that they exist in an aggregated beta sheet state as is common with other amyloid fibril forming peptides. Multiple single channel conductances were seen suggesting that various oligomers of beta 2M may be capable of forming channel structures. We suggest that beta 2M channel formation may account for some of the pathophysiologic effects seen in dialysis associated amyloidosis. These findings lend further weight to the "channel hypothesis" of amyloid pathogenesis.
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PMID:Pore formation by beta-2-microglobulin: a mechanism for the pathogenesis of dialysis associated amyloidosis. 1140 39

The available data on the pathophysiology of beta(2)-microglobulin amyloidosis (beta(2)mA) suggest that this progressive disease associated with end-stage renal failure develops in several consecutive phases. First, declining kidney function leads to retention of beta(2) microglobulin (beta(2)m) and its deposition preferentially in the synovial tissue of bigger joints such as wrists, shoulders, and hips. Second, at the site of deposition, formation of unique amyloid fibrils, whose major component is beta(2)m, takes place. Deposition and fibril formation occur in the absence of modification of beta(2)mA by advanced glycoxidation end products and also in the absence of a local inflammatory response. It is later, in the third phase, that advanced glycoxidation end product modification of beta(2)m induces a local inflammatory response by attracting macrophages chemotactically and by stimulating these cells to produce and release proinflammatory cytokines. In addition, unmodified beta(2)m itself induces inflammatory activities such as upregulation of cyclooxygenase-2 and metalloproteinase-1. The severity of the local inflammation seems to determine the degree of the destructive processes in tissue and bone accompanying beta(2)mA.
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PMID:Beta(2)-microglobulin amyloidosis: effects of ultrapure dialysate and type of dialyzer membrane. 1179 65

Serum amyloid A (SAA) activating factor-1 (SAF-1) is an inducible transcription factor that plays a key role in the regulation of several inflammation-responsive genes including SAA and matrix metalloproteinase-1. Increased synthesis of SAA and matrix metalloproteinase-1 is associated with pathogenesis of several diseases including amyloidosis, arthritis, and atherosclerosis. Previously, we showed in vivo interaction of SAF-1 and protein kinase A (PKA) and presented evidence for induction of SAF-1-regulated genes by a PKA signaling pathway. Here we demonstrate a mechanism by which PKA increases functional activities of SAF-1. Site-directed mutagenesis and phosphorylation analyses revealed two sites in the SAF-1 protein, serine 187 and threonine 386, as the target of PKA. Interestingly, mutation of both PKA phosphorylation sites created a highly active SAF-1 protein with high DNA-binding ability. Furthermore, we found that terminal deletion of SAF-1 protein from either end creates SAF-1 isoforms that are highly transcriptionally active. Partial proteolysis experiments indicated that unphosphorylated and phosphorylated SAF-1 proteins are structurally distinct. Together these results suggest that under native condition, N and C termini of SAF-1 are engaged in an inhibitory intramolecular interaction. PKA-mediated phosphorylation increases transcriptional activity of SAF-1 by unmasking the DNA-binding domain.
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PMID:Protein kinase A signaling pathway regulates transcriptional activity of SAF-1 by unmasking its DNA-binding domains. 1269 57


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