Cartilage destruction in arthritis: Mechanism of aggrecanase and matrix metalloproteinase action in vivo and in vitro

Funded Activity Summary

Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal development. However unregulated enzyme activity resulting in accelerated cartilage breakdown leads to the pathology recognised as arthritis. While some activities of the MMP and ADAMTS families have been studied in the laboratory, there have been no in vivo studies to determine which family is responsible for cartilage destruction, and which is therefore most appropriate for targeting by drugs. This project will create genetically-modified mice, resistant to either the MMP or the ADAMTS enzymes. The mice will be used in experimental arthritis models to determine which enzymes play the major role in initiating disease, which enzymes are involved in disease progression and which enzymes may be important for repair. In parallel studies, the highly specialised matrix molecule, keratan sulphate, will be studied for its role in cartilage destruction. There is preliminary evidence to suggest that keratan sulphate may be involved in the regulation of ADAMTS activity. The possible direct and indirect modalities of keratan sulphate action will be investigated. The results of this arthritis project will (a) yield new information on the mechanism of disease action; (b) identify targets for the rational design of disease-modifying drugs; (c) elucidate biochemical processes involved in normal skeletal growth and cartilage repair; and (d) provide new in vivo models for testing the efficacy of arthritis therapies.

Funded Activity Details

Start Date: 01-01-2001

End Date: 01-01-2005

Funding Scheme: NHMRC Project Grants

Funding Amount: $703,180.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Rheumatology And Arthritis

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

aggrecan degradation by ADAMTS proteinases | aggrecan degradation by matrix metalloproteinases | animal models of arthritis | cartilage destruction | cartilage extracellular matrix | glycosaminoglycan and keratan sulphate analysis | joint disease | osteoarthritis | rheumatoid arthritis

Related Links