Regulation of ADAMTS-5 activity by keratan sulphate-binding exosites

点击翻译按钮获取中文摘要

Arthritis and musculoskeletal conditions are the predominant cause of disability in Australia. The burden of arthritis is felt not only by patients, their families and carers, but also the labour market and the national economy. There is a pressing need to identify new targets for design of inexpensive arthritis therapies. The TNF antagonists have proved effective in managing rheumatoid arthritis (RA), but they are expensive, administered by injection, and in general, only prescribed in Australia for patients who respond poorly to DMARDs. Their long-term efficacy and safety is not yet determined. There are no treatments for osteoarthritis (OA), the disease that occurs more frequently with age and is characterised by destruction of cartilage and aggrecan. New drugs that protect against aggrecan breakdown are urgently needed for OA and they would also be valuable adjunct therapies to the DMARDs for treatment of RA. We have discovered that the major aggrecan-degrading enzyme is ADAMTS-5. ADAMTS-5 is, therefore, a potential target for arthritis therapies. Unfortunately, drugs targeting the active site of ADAMTS-5 are predicted to fail, given the wide tissue distribution of ADAMTS-5, the high level of homology between the active site of ADAMTS enzymes and matrix metalloproteinases (MMPs), and the notorious failure of MMP active site inhibitors in clinical trials. The aim of this project is to determine whether ancillary domains of ADAMTS-5 are a viable alternative target to the active site. We have evidence to suggest that keratan sulphate, which is covalently attached to the aggrecan core protein, can modulate aggrecan cleavage by ADAMTS enzymes. We aim to identify opportunities for developing antagonists that block keratan sulphate binding, or keratan sulphate analogues that block enzyme binding to its substrate. The data will inform the pharmaceutical industry on new directions for modulating aggrecanolysis by ADAMTS-5.