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Cartilage destruction in arthritis: Collagen and aggrecan-degrading proteinases

Lookup NU author(s): Emeritus Professor Drew Rowan, Emeritus Professor Tim Cawston

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Abstract

In the arthritic joint it is the extracellular matrix within the cartilage which is destroyed. It is therefore necessary to identify the proteinases responsible for both collagen and aggrecan cleavage. Interleukin 1 alpha (IL-1 alpha) can induce the release of collagen in a dose-dependent manner from bovine nasal cartilage in culture. In combination with oncostatin M (OM), even at IL-1 alpha concentrations which alone do not induce collagen loss, a marked synergistic release of collagen is observed. OM alone causes a rapid release of proteoglycan but only a slight loss of collagen. Time course experiments indicated that teatment with OM+IL-1 alpha resulted in release of 90% of the total collagen by day 10 of culture compared to a more variable loss in the presence of IL-1 alpha alone. Treatment with IL-1 beta as opposed to IL-1 alpha in combination with OM gave variable results in that although there was a reproducible synergistic release of GAG at day 7, the total loss of collagen appeared to be more variable. It is most likely that higher concentrations of IL-1 beta are required to produce the same effects that occur with lower levels of IL-1 alpha. Tumour necrosis factor alpha alone also gave a significant release of GAG but only a slight increase in collagen loss compared to the control, although when in combination with OM, almost all of the collagen was released by day 14 of culture. A quenched fluorescent substrate based on the major aggrecan cleavage site in the interglobular domain between the G1 and G2 domains using the sequence Gly-Glu-Gly-Glu-Ala-Arg-Gly-Ser was hydrolysed by a chondrocyte membrane preparation. Further analysis indicated that this substrate was cleaved between the Gly-Ser bond and not at the Glu-Ala site as would be predicted for aggrecanase. This activity, although not inhibited by tissue inhibitors of metalloproteinases-1 (TIMP-1), was inhibited by a metal chelator and was subsequently attributed to neprilysin, a plasma membrane-bound, zinc-containing enzyme known to be present on chondrocytes.


Publication metadata

Author(s): Rowan AD, Billington CJ, Knight CG, Cawston TE

Editor(s): Hawkes, SP; Edwards, DR; Khokha, R

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: Conference on Tissue Inhibitors of Metalloproteinases in Development and Disease

Year of Conference: 2000

Pages: 127-133

Publisher: Harwood Academic Publishers, Gmbh.

Library holdings: Search Newcastle University Library for this item

Series Title: Tissue Inhibitors of Metalloproteinases in Development and Disease

ISBN: 905702599X


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