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)

A central feature of the osteoarthritic disease process involves erosive destruction of the articular cartilage extracellular matrix (ECM) on the surfaces of diarthrotic joints. The resultant loss of joint function makes studies on mechanisms underlying ECM degradation critical for treatment of the disease and prevention of disability. Candidate pathways to account for the loss of cartilage involve expression of a combination of proteases that degrade the major cartilage matrix macromolecules, aggrecan and type II collagen. The specific types of enzymatic activities associated with the progressive removal of ECM and severity of joint disease include the matrix metalloproteinases, collagenase, gelatinase and aggrecanase(s). The degradative enzymes originate in synovial cells, cartilage cells, the chondrocytes, distributed within the ECM and leukocytes that actively invade the joint space. Specific enzymes arising from each of these tissues exhibit selective ECM degrading properties; the different categories of these tissue-derived enzymes will be discussed in this chapter. A perspective on the efficacy of existing agents and the potential for development of novel therapeutic agents is also included. While the degradative enzymes serve as a focal point for therapeutic intervention, a fundamental understanding of the mechanisms underlying degradative enzyme expression in osteoarthritis remains an important goal for prevention of disease.
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PMID:Degradative enzymes in osteoarthritis. 1052 83

The status of bronchial cartilage degeneration in chronic bronchitis is unclear, and little is known about the chondrolytic mechanisms involved. The potential contributions of various inflammatory cells, chondrocytes and cartilage-degrading enzymes to cartilage atrophy have been examined. Bronchial cartilage specimens were obtained at autopsy from lobar secondary bronchi from chronic bronchitics and age-matched controls; each was examined by light microscopy and immunohistology for the distributions of mast cells, macrophages, eosinophils, collagenase 1, collagenase 3, and degradation products of cartilage collagen. Most bronchitic specimens showed hypertrophic chondrocytes, some of which were immunostained for collagenase 3, and occasionally for collagenase 1. Evidence for collagen degradation products was demonstrated around the lacunae of a proportion of chondrocytes, and both collagenases were also observed in the soft inflammatory tissues in close association with the cartilage surface, together with variable distributions of mast cells and macrophages. Such observations were generally absent or very much reduced in the control, non-bronchitic specimens. Degenerative changes, atrophy and loss of bronchial cartilage were common features of most chronic bronchitic specimens, this usually being related to intrinsic changes in the chondrocyte phenotype, including proliferative and matrix-degrading properties. Mast cells and macrophages were often observed in close association with the bronchial cartilage, suggesting that inflammatory cells may also contribute to the mechanisms of bronchial cartilage degradation and loss. These observations of bronchial cartilage degeneration were generally lacking in age-matched non-bronchitic control specimens.
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PMID:Bronchial cartilage atrophy in chronic bronchitis: observations on chondrolytic processes. 1073 81

Matrix metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that can degrade all the proteins of the extracellular matrix and have been implicated in many abnormal physiological conditions including arthritis and cancer metastasis. Recently we have shown for the first time that the human MMP-1 gene is a p53 target gene subject to repression by wild type p53 (Sun, Y., Sun, Y. I., Wenger, L., Rutter, J. L., Brinckerhoff, C. E., and Cheung, H. S. (1999) J. Biol. Chem. 274, 11535-11540). Here, we report that cotransfection of fibroblast-like synoviocytes with p53 expression and hMMP13CAT reporter plasmids revealed that (i) hMMP13, another member of the human MMP family, was down-regulated by wild type p53, whereas all six of the p53 mutants tested lost the wild type p53 repressor activity in fibroblast-like synoviocytes; (ii) this repression of hMMP-13 gene expression by wild type p53 could be reversed by overexpression of p53 mutants p53-143A, p53-248W, p53-273H, and p53-281G; (iii) the dominant effect of p53 mutants over wild type p53 appears to be a promoter- and mutant-specific effect. An intriguing finding was that p53 mutant p53-281G could conversely stimulate the promoter activity of hMMP13 up to 2-4-fold and that it was dominant over wild type p53. Northern analysis confirmed these findings. Although the significance of these findings is currently unknown, they suggest that in addition to the effect of cytokines activation, the gene expression of hMMP13 could be dysregulated during the disease progression of rheumatoid arthritis (or cancer) associated with p53 inactivation. Since hMMP13 is 5-10 times as active as hMMP1 in its ability to digest type II collagen, the dysregulation or up-modulation of MMP13 gene expression due to the inactivation of p53 may contribute to the joint degeneration in rheumatoid arthritis.
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PMID:Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). 1075 45

Oncostatin M in combination with interleukin-1 (IL-1) induced a rapid and reproducible release of collagen from bovine nasal cartilage in culture. This release was accompanied by a high collagenolytic activity and low or absent tissue inhibitor of metalloproteinase-1 activity in the culture medium. Transforming growth factor-beta1 was able to block this release of collagen from the tissue, and reduce the expression and secretion of collagenases whilst maintaining TIMP-1 levels from bovine nasal chondrocytes. This study shows for the first time that TGF-beta1 can protect cartilage collagen from destruction.
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PMID:Transforming growth factor beta1 blocks the release of collagen fragments from boving nasal cartilage stimulated by oncostatin M in combination with IL-1alpha. 1084 61

The substrate specificity of human collagenase 3 (MMP-13), a member of the matrix metalloproteinase family, is investigated using a phage-displayed random hexapeptide library containing 2 x 10(8) independent recombinants. A total of 35 phage clones that express a peptide sequence that can be hydrolyzed by the recombinant catalytic domain of human collagenase 3 are identified. The translated DNA sequence of these clones reveals highly conserved putative P1, P2, P3 and P1', P2', and P3' subsites of the peptide substrates. Kinetic analysis of synthetic peptide substrates made from human collagenase 3 selected phage clones reveals that some of the substrates are highly active and selective. The most active substrate, 2, 4-dinitrophenyl-GPLGMRGL-NH(2) (CP), has a k(cat)/K(m) value of 4.22 x 10(6) m(-)(1) s(-)(1) for hydrolysis by collagenase 3. CP was synthesized as a consensus sequence deduced from the preferred subsites of the aligned 35 phage clones. Peptide substrate CP is 1300-, 11-, and 820-fold selective for human collagenase 3 over the MMPs stromelysin-1, gelatinase B, and collagenase 1, respectively. In addition, cleavage of CP is 37-fold faster than peptide NF derived from the major MMP-processing site in aggrecan. Phage display screening also selected five substrate sequences that share sequence homology with a major MMP cleavage sequence in aggrecan and seven substrate sequences that share sequence homology with the primary collagenase cleavage site of human type II collagen. In addition, putative cleavage sites similar to the consensus sequence are found in human type IV collagen. These findings support previous observations that human collagenase 3 can degrade aggrecan, type II and type IV collagens.
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PMID:Substrate specificity of human collagenase 3 assessed using a phage-displayed peptide library. 1090 30

The assembly and resorption of the extracellular matrix in the physis of the growth plate are poorly understood. By examining isolated fetal growth plate chondrocytes in culture and using immunochemical methods we show that type II collagen, proteoglycan aggrecan, and type IX collagen are assembled into a matrix that is initially enriched in type II collagen over proteoglycan and type IX collagen. When compared to the content of the COL2 domain in the alpha(1)(IX) chain it is evident that the majority ( 90%) of type IX molecules lack the NC4 domain unlike in articular cartilage. During matrix assembly the molar ratio of type II/COL2 of alpha(1)(IX) varied from 25:1 to 2.5:1. Following expression of the hypertrophic phenotype (initiation of type X collagen synthesis) there are parallel changes in both collagen and proteoglycan contents (inversely related to collagenase cleavage of type II collagen). The NC4 domain is then selectively, rapidly and irreversibly removed as mineralization is initiated, leaving the alpha(1)(IX) chain COL2 domain. Subsequently as mineralization progresses type II and type IX collagen (COL2 domain), but not the proteoglycan aggrecan, are resorbed coincident with a markedly increased cleavage of type II collagen by collagenase as mineral is deposited in the matrix. This study, therefore reveals a carefully orchestrated series of events in matrix assembly and resorption that prepares the extracellular matrix for mineralization.
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PMID:Selective assembly and remodelling of collagens II and IX associated with expression of the chondrocyte hypertrophic phenotype. 1090 83

Non-enzymic modification of tissue proteins by reducing sugars, the so-called Maillard reaction, is a prominent feature of aging. In articular cartilage, relatively high levels of the advanced glycation end product (AGE) pentosidine accumulate with age. Higher pentosidine levels have been associated with a stiffer collagen network in cartilage. However, even in cartilage, pentosidine levels themselves represent <1 cross-link per 20 collagen molecules, and as such cannot be expected to contribute substantially to the increase in collagen network stiffness. In the present study, we investigated a broad range of Maillard reaction products in cartilage collagen in order to determine whether pentosidine serves as an adequate marker for AGE levels. Not only did the well-characterized AGEs pentosidine, N(epsilon)-(carboxymethyl)lysine, and N(epsilon)-(carboxyethyl)lysine increase with age in cartilage collagen (all P<0.0001), but also general measures of AGE cross-linking, such as browning and fluorescence (both P<0.0001), increased. The levels of these AGEs are all higher in cartilage collagen than in skin collagen. As a functional measure of glycation the digestibility of articular collagen by bacterial collagenase was investigated; digestibility decreased linearly with age, proportional to the extent of glycation. Furthermore, the arginine content and the sum of the hydroxylysine and lysine content of cartilage collagen decrease significantly with age (P<0.0001 and P<0. 01 respectively), possibly due to modification by the Maillard reaction. The observed relationship between glycation and amino acid modification has not been reported previously in vivo. Our present results indicate that extensive accumulation of a variety of Maillard reaction products occurs in cartilage collagen with age. Altogether our results support the hypothesis that glycation contributes to stiffer and more brittle cartilage with advancing age.
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PMID:Age-related accumulation of Maillard reaction products in human articular cartilage collagen. 1094 51

The most abundant macromolecules in cartilage are hyaluronan, collagen, aggrecan, and link protein, which are believed to play roles in maintaining a unique three-dimensional network for a functional joint. This study was designed to investigate the roles of the major extracellular molecules in mediating chondrocyte-matrix interactions. We employed specific approaches to remove components individually or in combination: hyaluronan was digested with hyaluronidase; type II collagen was digested with collagenase; aggrecan expression was inhibited with antisense and beta-xyloside approaches; and link protein expression was inhibited with antisense oligonucleotides. Digestion of hyaluronan induced chondrocyte attachment to tissue culture plates, collagen-coated plates, and fibroblast-like chondrocyte cultures, and induced chondrocyte aggregation. Treated chondrocytes exhibited a fibroblast-like morphology, and the effects of hyaluronidase were dose-dependent. Conversely, the effect of collagenase on chondrocyte adhesion and aggregation was far less pronounced. Treatment with Arg-Gly-Asp peptide inhibited chondrocyte-collagen interaction. Chondrocyte attachment was enhanced by antisense oligonucleotides complementary to aggrecan and link protein and by beta-xyloside treatment. Nevertheless, hyaluronan seems to predominate over the other molecules in mediating chondrocyte-matrix interactions.
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PMID:The roles of matrix molecules in mediating chondrocyte aggregation, attachment, and spreading. 1096 59

Retinoic acid (RetA) and interleukin-1alpha (IL-1) together can induce a reproducible release of proteoglycan fragments from bovine nasal cartilage in culture. However, release of collagen fragments with either agent alone is often variable. In this study over 70% of the total collagen was released from bovine nasal cartilage in culture by day 14 when RetA and IL-1 were combined. This release was accompanied by the appearance of collagenolytic activity in the culture medium that cleaved collagen specifically at the (1/4)/(3/4) position. Tissue inhibitor of metalloproteinases (TIMP) activity was present at day 7 but low or absent in media from resorbing tissue at day 14. The breakdown of cartilage collagen could be prevented by the addition of BB-94, a specific metalloproteinase inhibitor. These results suggest that RetA promotes the early release of TIMP from the tissue and that IL-1 stimulates pro-collagenase secretion which, when activated, exceeds the local concentration of TIMP. Thus in the later stages of culture collagen destruction occurs. Both MMP-1 and MMP-13 were detected and appear to be involved in IL-1 + RetA induced bovine cartilage destruction. However, for the first time, we also present evidence to suggest that MMP-13 is the predominant collagenase in this system.
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PMID:Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: matrix metalloproteinases-1 and -13 are involved in cartilage collagen breakdown. 1099 43

Excessive mechanical load is thought to be responsible for the onset of osteoarthrosis (OA), but the mechanisms of cartilage destruction caused by mechanical loads remain unknown. In this study we applied a high magnitude cyclic tensile load to cultured chondrocytes using a Flexercell strain unit, which produces a change in cell morphology from a polygonal to spindle-like shape, and examined the protein level of cartilage matrixes and the gene expression of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs) and proinflammatory cytokines such as IL-1beta and TNF-alpha. Toluidine blue staining, type II collagen immunostaining, and an assay of the incorporation of [35S]sulfate into proteoglycans revealed a decrease in the level of cartilage-specific matrixes in chondrocyte cultures subjected to high magnitude cyclic tensile load. PCR-Southern blot analysis showed that the high magnitude cyclic tensile load increased the mRNA level of MMP-1, MMP-3, MMP-9, IL-1beta, TNF-alpha and TIMP-1 in the cultured chondrocytes, while the mRNA level of MMP-2 and TIMP-2 was unchanged. Moreover, the induction of MMP-1, MMP-3 and MMP-9 mRNA expression was observed in the presence of cycloheximide, an inhibitor of protein synthesis. These findings suggest that excessive mechanical load directly changes the metabolism of cartilage by reducing the matrix components and causing a quantitative imbalance between MMPs and TIMPs.
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PMID:The effects of high magnitude cyclic tensile load on cartilage matrix metabolism in cultured chondrocytes. 1104 1


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