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Inhibition of furin-like enzymes blocks interleukin-1 alpha/oncostatin M-stimulated cartilage degradation

Lookup NU author(s): Dr Jenny Milner, Emeritus Professor Drew Rowan, Dr Sarah Elliott, Emeritus Professor Tim Cawston


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Objective. To investigate the role of furin-like enzymes in the proteolytic cascades leading to cartilage breakdown and to examine which collagenase(s) contribute to collagen degradation. Methods. Bovine nasal cartilage was stimulated to resorb with the addition of interleukin-1alpha (IL-1alpha)/oncostatin M (OSM) in the presence or absence of a furin inhibitor, Dec-RVKR-CH2Cl or selective matrix metalloproteinase 1 (MMP-1) inhibitors. Collagen and proteoglycan levels were determined by assay of hydroxyproline and sulfated glycosaminoglycan, respectively. Collagenase and gelatinase activity were measured using H-3-acetylated collagen and gelatin zymography, respectively. Results. The addition of Dec-RVKR-CH2Cl to stimulated cartilage reduced the release of collagen. fragments and the levels of active collagenase and MMP-2, suggesting that furin-like enzymes are involved in the cascades leading to activation of procollagenases. At MMP inhibitor concentrations that selectively inhibit MMP-1, no inhibition of collagen release was observed, but increasing the concentration to the 50% inhibition concentration for MMP-13 resulted in a 50% blockage of collagen release. The addition of Dec-RVKR-CH2Cl to resorbing cartilage also partially blocked proteoglycan release, thus demonstrating a role for furin-activated enzymes in the pathways leading to proteoglycan degradation. Conclusion. Furin-like enzymes are involved in cascades leading to activation of procollagenases and degradation of collagen. MMP-13, which can be activated by furin-processed membrane-type 1 MMP-1, appears to be a major collagenase involved in collagen degradation induced by IL-1alpha/OSM. Furin-like enzymes also appear to play a role in the pathways leading to proteoglycan degradation. These findings are of importance when considering proteinase inhibition as a target for therapeutic intervention in arthritic diseases.

Publication metadata

Author(s): Milner JM, Rowan AD, Elliott SF, Cawston TE

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatism

Year: 2003

Volume: 48

Issue: 4

Pages: 1057-1066

ISSN (print): 0004-3591

ISSN (electronic): 1529-0131

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/art.10873


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