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Lookup NU author(s): Emeritus Professor Drew Rowan,
Emeritus Professor Tim Cawston
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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.
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
Publisher: Harwood Academic Publishers, Gmbh.
Library holdings: Search Newcastle University Library for this item
Series Title: Tissue Inhibitors of Metalloproteinases in Development and Disease