The effects of anti-inflammatory drugs on cartilage breakdown and their mechanism of action chondrocytes

Lakey, Rachel Louisa (2008) The effects of anti-inflammatory drugs on cartilage breakdown and their mechanism of action chondrocytes. Doctoral thesis, Northumbria University.

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Abstract

The progressive loss of cartilage matrix is a major characteristic of arthritic disease, ultimately leading to a loss of joint function. A number of therapeutics are used in the treatment of arthritic disease, with non-steroidal anti-inflammatory drugs used to treat the pain and inflammation seen in osteoarthritis and rheumatoid arthritis, whilst disease modifying anti-rheumatic drugs are used to slow disease progression. However it is not fully understood if and how many of these drugs effect the disease processes in arthritis. The objective of this study is to look at a number of therapeutics and investigate their effect on the breakdown of proteoglycan and collagen, and on the expression of a number of key degradation enzymes, whilst trying to identify the possible mechanisms used by the drugs. Using the bovine nasal cartilage explant model IL-1 + OSM were used to stimulate the release of proteoglycan and collagen from the cartilage. Interleukin-1 (IL-1) and oncostatin M (OSM) together promote the degradation of cartilage by up regulating and activating MMPs that are found within the diseased joint. Treatment of the resorbing cartilage with indomethacin, indomethacin heptyl ester, simvastatin, mevastatin, pravastatin and sulfasalazine produced a variation of findings with many resulting in the inhibition of cartilage degradation. The stimulation of human articular chondrocytes with IL-1 + OSM caused a significant up regulation of MMPs by the cells at both a gene and protein level when measured by TaqMan PCR and ELISA respectively. Again treatment of the stimulated chondrocytes with a number of the drugs showed a significant reduction in the expression of key cartilage degrading enzymes. The investigation of signalling mechanisms affected by one specific drug, namely sulfasalazine by immunoblotting and signalling microarray, showed some interesting results not previously documented. Sulfasalazine is well known to inhibit NF-I(13 activation by blocking the degradation of IicB to the proteosome and data in this study supports these finding. However, study of the MAPK pathway showed that sulfasalazine appears to be able to block the signalling cascade which ultimately leads to AP-1 activation in chondrocytes stimulated with IL-1 + OSM. This study has identified possible chondroprotective properties in a number of the drugs which were screened and whilst the exact mechanisms behind these events still require further investigation, the results highlight the potential of these drugs in being used to prevent further cartilage degradation in arthritis and thus further delaying the possible need for joint replacement operations.

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