Abstract
Metalloproteinases such as the matrix metalloproteinases (MMPs) and disintegrin-metalloproteinases with thrombospondin motifs (ADAMTSs) have been implicated in the pathological destruction of joint tissues in rheumatoid arthritis and osteoarthritis. These enzymes degrade extracellular matrix macromolecules and modulate factors governing cell behavior. They may also be involved in tissue repair, but become a part of the destructive disease process due to overexpression. Studies investigating the roles of metalloproteinases have thrown light on the failure of the early clinical trials of MMP inhibitors as therapeutic agents in arthritic diseases. It is now clear that a more accurate knowledge of the enzymes in the different cells and their precise roles in the disease process is required for these approaches to be successful. The next generations of metalloproteinase inhibitors should have added specificity, gained from an understanding not only of the catalytic domain structures but the role of extracatalytic motifs in substrate binding, or by the generation of engineered tissue inhibitors of metalloproteinases. Inhibition of the enzymes by modulating gene expression or preventing protein activation could also be considered. Work on the development of effective biomarkers is also essential before an effective evaluation of the new generations of specific inhibitors can be made.
Key Points
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Matrix metalloproteinases and disintegrin metalloproteinases with thrombospondin motifs elevated in joint tissues in rheumatoid arthritis (RA) and osteoarthritis (OA) are the key enzymes that degrade the extracellular matrix of cartilage
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In RA metalloproteinases are derived primarily from inflammatory cytokine stimulated synovial lining cells, whereas in OA the enzymes arise from chondrocytes and inductive stimuli include mechanical stress, tissue injury, oxidative stress, degraded matrix, joint destabilization and aging, as well as inflammatory cytokines
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Clinical trials of matrix metalloproteinases inhibitors have not been successful, probably because of the lack of selectivity of the inhibitors. Highly selective, nontoxic compounds are essential for metalloproteinase inhibitor therapy of arthritis
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It may be possible to develop of selective inhibitors based on molecules that interact with the exosite of the enzyme, allosteric inhibitors, or engineering of tissue inhibitors of metalloproteinases
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Biomarkers to monitor the in vivo efficacy of metalloproteinase inhibitors are necessary
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Acknowledgements
Work was supported by grants from the Medical Research Council, Cancer Research UK and European Union Framework 5 Programme and 6 Programme to GM, and from the Wellcome Trust, Arthritis Research Campaign and National Institutes of Health to HN.
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Murphy, G., Nagase, H. Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair?. Nat Rev Rheumatol 4, 128–135 (2008). https://doi.org/10.1038/ncprheum0727
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DOI: https://doi.org/10.1038/ncprheum0727
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