Metalloproteases as potential therapeutic targets in arthritis treatment

Abstract

Dysregulated proteolysis of the extracellular matrix of articular cartilage represents a unifying hallmark of the arthritides, and has been a target for therapeutic intervention for some time, although clinical efficacy has been elusive. Members of the ‘A disintegrin and metalloprotease with thrombospondin motifs’ and matrix metalloprotease families are considered to be collectively responsible for cartilage catabolism, such that inhibition of these activities is theoretically a highly attractive strategy for preventing further proteolytic damage. This review outlines the biology of these metalloproteases and what we have learnt from inhibition studies and transgenics, and highlights the important questions that this information raises for the future development of therapeutics directed towards metalloproteases for arthritis treatment.

Keywords::

• A disintegrin and metalloprotease with thrombospondin motifs
• arthritis
• cartilage
• matrix metalloprotease
• tissue inhibitor of metalloproteases
• transcription
• signalling pathways

Acknowledgements

We are also grateful to Dr Graham Riley (Addenbrooke's Hospital, Cambridge) and Prof Ian Clark (University of East Anglia, UK) for their critical reading of the manuscript.