Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation

被引:115
作者
Sondergaard, B. C.
Henriksen, K.
Wulf, H.
Oestergaard, S.
Schurigt, U.
Brauer, R.
Danielsen, I.
Christiansen, C.
Qvist, P.
Karsdal, M. A.
机构
[1] Nord Biosci Diagnost, DK-2730 Herlev, Denmark
[2] Pharmos Biosci, Herlev, Denmark
[3] Univ Jena, Dept Pathol, D-6900 Jena, Germany
[4] Ctr Clin & Basic Res, Ballerup, Denmark
关键词
articular cartilage; collagen type II fragments; CTX-II; TNF-alpha; oncostatin M; matrix metalloproteases; cathepsin K;
D O I
10.1016/j.joca.2006.01.016
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
Objective: Both matrix metalloprotease (MMP) activity and cathepsin K (CK) activity have been implicated in cartilage turnover. We investigated the relative contribution of MMP activity and CK activity in cartilage degradation using ex vivo and in vivo models. Methods: Bovine articular cartilage explants were stimulated with oncostatin M (OSM) 10 ng/ml and tumor necrosis factor-alpha (TNF-alpha) 20 ng/ml in the presence or absence of the broad-spectrum MMP inhibitor GM6001 and the cysteine protease inhibitor, E64. Cartilage degradation was evaluated in the conditioned medium by glycosaminoglycans (GAG), hydroxyproline, and cross-linked C-telopeptide fragments of type II collagen (CTX-II), which were compared to immunohistochemical evaluations of proteoglycans and CTX-II. We assessed MMP expression by gelatine zymography and CK expression by immunohistochemistry. In vivo, CTX-II release was measured from CK-deficient mice. Results: OSM and TNF-alpha combined induced significant (P < 0.01) increase in cartilage degradation products measured by hydroxyproline and CTX-II compared to vehicle control. The cytokines potently induced MMP expression, assessed by zymography, and CK expression investigated by immunohistochemistry. Inhibition of MMP activity completely abrogated hydroxyproline and CTX-II release (P < 0.01) and GAG release (P< 0.05). In contrast, E64 resulted in increased CTX-II release by 100% (P< 0.05) and inhibited GAG release by 30%. Up-regulation of CTX-II fragments was confirmed in vivo in CK null mice. Conclusion: Inhibition of MMP activity reduced both proteoglycan loss and type II collagen degradation. In contrast, inhibition of cysteine proteases resulted in an increase rather than a decrease in MMP derived fragments of collagen type II degradation, CTX-II, suggesting altered collagen metabolism. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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收藏
页码:738 / 748
页数:11
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