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.

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.

Interleukin-1 beta induces interstitial collagenase gene expression and protein secretion in renal mesangial cells

1995 ◽  
Vol 269 (6) ◽  
pp. F831-F837 ◽  
Author(s):  
D. Daphna-Iken ◽  
A. R. Morrison
Keyword(s):  
Matrix Metalloproteinase ◽  
Mesangial Cells ◽  
Interleukin 1 ◽  
Active Form ◽  
Cdna Probe ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Mrna Levels ◽  
Interleukin 1 Beta ◽  
Mrna Induction ◽  
Interstitial Collagenase

Degradation and tissue remodeling of the extracellular matrix in the normal glomerulus occur through the coordinate action of neutral metalloproteinases, which are in turn regulated by specific inhibitors. Many of these proteins can be secreted by mesangial cells. In the current study, gene regulation of a rat matrix metalloproteinase, interstitial collagenase and its tissue inhibitor of metalloproteinase-1 (TIMP-1), was investigated by Northern blot analysis. Stimulation of rat mesangial cell (RMC) collagenase by interleukin 1 beta (IL-1 beta) produced an increase (> 45-fold) in mRNA which peaked at 12 h. Lesser effects on the TIMP-1 mRNA expression were observed in response to IL-1 beta. Indomethacin did not influence the effect of IL-1 beta on collagenase, and exogenous prostaglandin E2 had no significant effect either on basal or IL-1 beta-stimulated mRNA levels. Collagenase was secreted into the media and showed minimal gelatinolytic activity at 36-h stimulation with IL-1 beta by zymography. By Western immunoblotting, we demonstrated with 24 h of stimulation the secretion of the active form of collagenase, which further increased after 36 h with IL-1 beta compared with the control. When RMC were retreated with genistein and herbimycin A, both inhibited collagenase mRNA induction by IL-1 beta. These data suggest that IL-1 beta stimulates interstitial collagenase synthesis and activation and that a tyrosine kinase pathway is involved in the signal transduction mechanisms and is not dependent on endogenous prostaglandin biosynthesis. Recently, a third interstitial collagenase (collagenase-3) has been identified from breast carcinoma. This cDNA is 84% identical to the rat interstitial collagenase cDNA probe we have utilized in this study and thus may represent the rat homologue of the human collagenase-3 now called matrix metalloproteinase (MMP)-13.

scholarly journals Treatment of Bovine Nasal Cartilage Proteoglycan with Chondroitinases from Flavobacterium heparinum and Proteus vulgaris

1972 ◽  
Vol 247 (14) ◽  
pp. 4521-4528 ◽  
Author(s):  
Vincent C. Hascall ◽  
Rick L. Riolo ◽  
James Hayward ◽  
Clifford C. Reynolds
Keyword(s):  
Proteus Vulgaris ◽  
Nasal Cartilage ◽  
Cartilage Proteoglycan ◽  
Flavobacterium Heparinum

scholarly journals Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1? in human tendon-derived cells

2002 ◽  
Vol 46 (11) ◽  
pp. 3034-3040 ◽  
Author(s):  
Anthony N. Corps ◽  
Rebecca L. Harrall ◽  
Valerie A. Curry ◽  
Steven A. Fenwick ◽  
Brian L. Hazleman ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Interleukin 1 ◽  
Matrix Metalloproteinase 3 ◽  
Human Tendon ◽  
Stimulation Of
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