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Osteoarthritis (OA) affects approximately 20% of Australians and costs billions each year in joint replacements. Therapies that halt joint destruction in OA are urgently needed. We hypothesise that the little-known gene, vanin -3, is a key regulator of OA disease pathways. Our project will map vanin-3 in the joint and reveal how much vanin-3 contributes to joint destruction in mice. We expect to find a link between vanin-3 and metabolic disorders and identify new targets for therapy.
Effect Of Lifestyle Factors On Knee Cartilage Volume And Rate Of Cartilage Loss In A Normal Population
Funder
National Health and Medical Research Council
Funding Amount
$236,500.00
Summary
Osteoarthritis (OA) has been described by the WHO as a potential epidemic and a major health and care services cost driver in an aging society. OA has the largest impact on burden of disease borne in later life. This has been acknowledged by its listing as the 7th health priority in Australia. To date, most research has focused on treating the resulting pain and disability. However, in order to reduce the burden of OA, identifying modifiable risk factors in the normal population is important. Th ....Osteoarthritis (OA) has been described by the WHO as a potential epidemic and a major health and care services cost driver in an aging society. OA has the largest impact on burden of disease borne in later life. This has been acknowledged by its listing as the 7th health priority in Australia. To date, most research has focused on treating the resulting pain and disability. However, in order to reduce the burden of OA, identifying modifiable risk factors in the normal population is important. This proposal aims to identify life-style factors, such as diet, physical activity and obesity that effect knee cartilage health in healthy subjects, thereby identifying potential targets for future prevention of OA. This will provide us with the opportunity to promote a better quality of life as people age and reduce the economic burden on the community.Read moreRead less
A Long Term Follow-up Of The Offspring Cohort: A Controlled Study Of Those At Higher Risk Of Knee Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$238,168.00
Summary
Osteoarthritis is the most common musculoskeletal disorder. Despite this, relatively little is known about how the disease develops. This study will use a powerful technique known as MRI scanning to determine the sequence of changes over 10 years in subjects at higher risk of osteoarthritis (based on their family history) but who do not yet have established disease on radiographs (even though many have symptoms).
How Important Is Collagen Destruction In Arthritis? A Study With Collagenase-resistant Knockin Mice
Funder
National Health and Medical Research Council
Funding Amount
$529,723.00
Summary
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is n ....Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.Read moreRead less
Regulation Of ADAMTS-5 Activity By Keratan Sulphate-binding Exosites
Funder
National Health and Medical Research Council
Funding Amount
$213,342.00
Summary
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 Australi ....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.Read moreRead less
Improving The Prevention And Outcomes Of Knee And Hip Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
Osteoarthritis is a major public health problem. No current treatment slows disease progression with end-stage osteoarthritis treated by joint replacement surgery. This project will identify new approaches for the prevention and treatment of osteoarthritis and the improvement of patients’ outcomes after total joint replacement surgery. The findings will have both public health and clinical impact, informing clinical practice of strategies to improve the prevention and outcomes of osteoarthritis.