scholarly journals Lysosomal cysteine endopeptidases mediate interleukin 1-stimulated cartilage proteoglycan degradation

1992 ◽  
Vol 287 (2) ◽  
pp. 657-661 ◽  
Author(s):  
D J Buttle ◽  
J Saklatvala
Keyword(s):  
Interleukin 1 ◽  
Active Form ◽  
Growth Factor Receptor ◽  
Test System ◽  
Significant Inhibition ◽  
Cartilage Explants ◽  
Cartilage Proteoglycan ◽  
Proteoglycan Degradation ◽  
Cysteine Endopeptidases ◽  
Proteoglycan Release

The peptidyl diazomethane inactivator of cysteine endopeptidases, benzyloxycarbonyl-Tyr-Ala-CHN2, was tested as an inhibitor of interleukin 1 alpha-stimulated release of proteoglycan from bovine nasal septum cartilage explants. Like the previously tested epoxidyl peptide proinhibitor trans-epoxysuccinyl-leucylamido-(3-methyl)butane ethyl ester, it proved to be an effective inhibitor of proteoglycan release from cartilage, with significant inhibition at a concentration of 1 microM. The inhibition did not seem to be due to a general toxic effect. The rates of inactivation of the bovine cysteine endopeptidases by the peptidyl diazomethane, the epoxidyl peptide proinhibitor and its active form were determined. Benzyloxycarbonyl-Tyr-Ala-CHN2 proved to be a rapid inactivator of cathepsins L, S and B, but reacted much more slowly with cathepsin H and calpain. Thus it would appear that the latter two enzymes are not implicated in proteoglycan release in our test system. The peptidyl diazomethane and epoxidyl peptide proinhibitor (above) were also tested for their effects on three other interleukin 1-mediated cellular events, namely epidermal growth factor receptor transmodulation, and interleukin 6 and prostaglandin E2 production. In all cases the inactivators did not interfere with the response to interleukin 1 in human gingival fibroblasts. We conclude that one or more of the lysosomal cysteine endopeptidases cathepsins B, L and S mediate interleukin 1-stimulated cartilage proteoglycan degradation without affecting signal transduction.

scholarly journals Inhibition of interleukin 1-stimulated cartilage proteoglycan degradation by a lipophilic inactivator of cysteine endopeptidases

1992 ◽  
Vol 281 (1) ◽  
pp. 175-177 ◽  
Author(s):  
D J Buttle ◽  
J Saklatvala ◽  
M Tamai ◽  
A J Barrett
Keyword(s):  
Interleukin 1 ◽  
Test System ◽  
Significant Inhibition ◽  
Detectable Effect ◽  
Inhibitory Effects ◽  
Proteoglycan Degradation ◽  
Cysteine Endopeptidases ◽  
Cartilage Breakdown ◽  
Pass Through ◽  
Proteoglycan Release

Inactivators of cysteine endopeptidases were tested as inhibitors of the cytokine-stimulated release of proteoglycan from cartilage. The test system consisted of bovine nasal septum cartilage maintained in organ culture, and the stimulus was provided by recombinant human interleukin 1 alpha. L-3-Carboxy-2,3-trans-epoxypropionyl-leucylamido-(4-guanidin o)butane (E64) and L-3-carboxy-2,3-trans-epoxypropionyl-leucylamido-(3-methyl)b utane (Ep475) showed no inhibition at concentrations up to 100 microM. In contrast, trans-epoxysuccinyl-leucylamido-(3-methyl)butane ethyl ester (Ep453), a ‘prodrug’ of Ep475, was an effective inhibitor. The LL-, LD- and DL-isomers gave significant inhibition at 10 microM, and the DD-isomer was inhibitory at 100 microM. None of the isomers had any detectable effect on protein synthesis or glycolysis, and their inhibitory effects were reversible. Iodoacetate inhibited proteoglycan release by a general toxic effect. Our results suggest that cysteine endopeptidase(s) play a part in cytokine-stimulated cartilage breakdown, but that effective inhibitors must pass through membranes.

scholarly journals Isothiazolones interfere with normal matrix metalloproteinase activation and inhibit cartilage proteoglycan degradation

1996 ◽  
Vol 318 (2) ◽  
pp. 417-424 ◽  
Author(s):  
Elizabeth C ARNER ◽  
Michael A PRATTA ◽  
Bruce FREIMARK ◽  
Michael LISCHWE ◽  
James M TRZASKOS ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Interleukin 1 ◽  
Active Form ◽  
Activation Process ◽  
Terminal Sequence ◽  
Nasal Cartilage ◽  
Cartilage Proteoglycan ◽  
Acid Cleavage ◽  
Sds Page ◽  
Proteoglycan Degradation

A series of isothiazolones that inhibit pro-(matrix metalloproteinase) (proMMP) activation but do not inhibit the active enzyme are effective as cartilage protectants in bovine nasal cartilage organ culture, preventing interleukin-1 (IL-1)-induced proteoglycan (aggrecan) degradation without affecting its synthesis. These compounds were found to bind to prostromelysin (proMMP-3) in a non-dialysable and stoichiometric manner. Preincubation with cartilage-protectant isothiazolones prevented the binding of [14C]iodoacetamide to Cys75 of the MMP-3 propeptide, suggesting that the activity of these compounds involves their binding to the Cys75 of the MMP zymogen. Studies following chymotrypsin activation of proMMP-3 by SDS/PAGE indicated that altered processing of the 57 kDa zymogen to the active form occurred in the presence of compound. The 53 kDa intermediate seen on normal activation was not formed; instead a different intermediate appeared with a molecular mass of approx. 46 kDa. N-terminal sequence analysis indicated that this intermediate was formed by cleavage at the putative 4-aminophenylmercuric acid cleavage site. Importantly the 45 kDa active MMP-3 species formed in the presence of compound was one amino acid residue shorter than the native MMP-3. These results suggest that the inhibition of cartilage proteoglycan degradation by isothiazolones might be due to their ability to bind to the Cys75 in the propeptide region of the MMP zymogen and interfere with its normal activation process.

Interleukin 1-stimulated cartilage proteoglycan degradation is inhibited by some cysteine endopeptidase inactivators

Cytokine ◽  
1991 ◽  
Vol 3 (5) ◽  
pp. 499
Author(s):  
David J. Buttle ◽  
Jeremy Saklatvala ◽  
Alan J. Barrett
Keyword(s):  
Interleukin 1 ◽  
Cysteine Endopeptidase ◽  
Cartilage Proteoglycan ◽  
Proteoglycan Degradation

Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin b and an inhibitor of matrix metalloproteinases. evidence for two converging pathways of chondrocyte-mediated proteoglycan degradation

1993 ◽  
Vol 36 (12) ◽  
pp. 1709-1717 ◽  
Author(s):  
David J. Buttle ◽  
Christopher J. Handley ◽  
Mirna Z. Ilic ◽  
Jeremy Saklatvala ◽  
Mitsuo Murata ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Cathepsin B ◽  
Cartilage Proteoglycan ◽  
Proteoglycan Degradation ◽  
Proteoglycan Release

scholarly journals Thyroid Hormone Enhances Aggrecanase-2/ADAM-TS5 Expression and Proteoglycan Degradation in Growth Plate Cartilage

Endocrinology ◽  
2003 ◽  
Vol 144 (6) ◽  
pp. 2480-2488 ◽  
Author(s):  
Seicho Makihira ◽  
Weiqun Yan ◽  
Hiroshi Murakami ◽  
Masae Furukawa ◽  
Toshihisa Kawai ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Growth Plate ◽  
Cleavage Site ◽  
Endochondral Ossification ◽  
Core Protein ◽  
Binding Capacity ◽  
Mrna Level ◽  
Cartilage Explants ◽  
Type I ◽  
Proteoglycan Degradation

Abstract Effects of thyroid hormone on proteoglycan degradation in various regions of cartilage were investigated. In propylthiouracil-treated rats with hypothyroidism, proteoglycan degradation in epiphyseal cartilage during endochondral ossification was markedly suppressed. However, injections of T4 reversed this effect of propylthiouracil on proteoglycan degradation. In pig growth plate explants, T3 also induced breakdown of proteoglycan. T3 increased the release of aggrecan monomer and core protein from the explants into the medium. Accordingly, the level of aggrecan monomer remaining in the tissue decreased after T3 treatment, and the monomer lost hyaluronic acid-binding capacity, suggesting that the cleavage site is in the interglobular domain. The aggrecan fragment released from the T3-exposed explants underwent cleavage at Glu373-Ala374, the major aggrecanase-cleavage site. The stimulation of proteoglycan degradation by T3 was less prominent in resting cartilage explants than in growth plate explants and was barely detectable in articular cartilage explants. Using rabbit growth plate chondrocyte cultures, we explored proteases that may be involved in T3-induced aggrecan degradation and found that T3 enhanced the expression of aggrecanase-2/ADAM-TS5 (a disintegrin and a metalloproteinase domain with thrombospondin type I domains) mRNA, whereas we could not detect any enhancement of stromelysin, gelatinase, or collagenase activities or any aggrecanase-1/ADAM-TS4 mRNA expression. We also found that the aggrecanse-2 mRNA level, but not aggrecanase-1, increased at the hypertrophic stage during endochondral ossification. These findings suggest that aggrecanse-2/ADAM-TS5 is involved in aggrecan breakdown during endochondral ossification, and that thyroid hormone stimulates the aggrecan breakdown partly via the enhancement of aggrecanase-2/ADAM-TS5.

scholarly journals Interleukin 1 beta and Matrix Metallopeptidase 3 Contribute to Development of Epidermal Growth Factor Receptor–Dependent Serrated Polyps in Mouse Cecum

2019 ◽  
Vol 157 (6) ◽  
pp. 1572-1583.e8 ◽  
Author(s):  
Zhengxiang He ◽  
Lili Chen ◽  
Grace Chen ◽  
Paola Smaldini ◽  
Gerold Bongers ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Interleukin 1 ◽  
Growth Factor Receptor ◽  
Interleukin 1 Beta ◽  
Serrated Polyps ◽  
Matrix Metallopeptidase ◽  
Epidermal Growth ◽  
Mouse Cecum
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