Signalling Through A Bioactive Aggrecan Fragment: What Is The Mechanism?
Funder
National Health and Medical Research Council
Funding Amount
$431,347.00
Summary
Osteoarthritis (OA) affects approximately 20% of Australians. There are no therapies that modify the course of the disease and joint replacement surgery is expensive and invasive. We have discovered that a peptide product of cartilage breakdown (the 32mer) signals cartilage cells to mount an inflammatory and catabolic response. We will determine how the 32mer triggers this response, whether other joint cells are similarly activated and how it can be stopped, with the goal of pursuing new targets ....Osteoarthritis (OA) affects approximately 20% of Australians. There are no therapies that modify the course of the disease and joint replacement surgery is expensive and invasive. We have discovered that a peptide product of cartilage breakdown (the 32mer) signals cartilage cells to mount an inflammatory and catabolic response. We will determine how the 32mer triggers this response, whether other joint cells are similarly activated and how it can be stopped, with the goal of pursuing new targets for therapyRead moreRead less
Tissue Engineering Approach To Musculoskeletal Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$622,655.00
Summary
Over the next few decades there is an anticipated steady increase in surgical intervention for bone, cartilage and tendon damages due to trauma or osteoporosis as a consequence of an aging population. These damages cause chronic pain, immobility, restricted activities, and, sometimes, death and are a considerable financial burden to the Australian Health System.
MicroRNAs As Therapeutic Targets For Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$921,754.00
Summary
microRNAs are small cellular RNA fragments that regulate protein expression. They have been shown to be crucial regulators of normal development and are associated with many disease processes. The goal of this project is to determine the role of microRNAs in the initiation and progression of joint degeneration in osteoarthritis and test the therapeutic efficacy of targeting microRNAs as new approach to OA treatment.
ARC, A Newly Identified Regulator Of Chondrocyte Differentiation And Death, Is A Novel Therapeutic Target For OA
Funder
National Health and Medical Research Council
Funding Amount
$763,983.00
Summary
We have identified a critical regulator of the survival and normal metabolism of the cells in articular cartilage. Loss of this molecule is an early event in joint injury that leads to osteoarthritis (OA). The current proposal will determine the mechanisms whereby this protein functions to protect cartilage breakdown in OA, how its levels in chondrocytes are regulated in both healthy and diseased conditions, and at what stages of disease increasing its expression protects against OA progression.
The Therapeutic Value Of Targeting Wnt Signalling For The Treatment Of Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$561,535.00
Summary
Osteoarthritis (OA) affects 1.62 million Australians and imposes a significant burden on healthcare. It is characterised by damage to joint cartilage, and increased bone formation with formation of bone spurs. Our studies will determine the importance of the Wnt signalling pathway in mediating OA joint degeneration and identify mechanisms that regulate the activation of this pathway in OA. This will inform the development of novel therapeutic strategies which could halt joint damage in OA.
Molecular Mechanisms Of Joint Degeneration In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$718,273.00
Summary
Arthritis is a major clinical and socio-economic problem. Arthritis involves the destruction of cartilage in joints. However, the mechanisms of initiation and progression of cartilage destruction remain poorly understood. Our studies will for explore the role of a new regulator of gene expression, microRNA, in the initation and progression of osteoarthritis. This will provide important new information on disease mechanisms for the development of diagnostic biomarkers and therapies
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
Pathobiology Of The Small Leucine Rich Repeat Proteoglycans In Cartilage, Intervertebral Disc And Tendon Degeneration
Funder
National Health and Medical Research Council
Funding Amount
$516,625.00
Summary
Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common cause of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3 billion) and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million prescriptions. Significant disability due to MSK disease were noted in ~50% of peopl ....Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common cause of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3 billion) and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million prescriptions. Significant disability due to MSK disease were noted in ~50% of people aged 65 years. Australian census data indicates that ageing trends will result in an increased incidence of MSK conditions as the longevity of the Australian population rises, exerting an ever increasing burden on the healthcare budget. Extreme levels of sporting or physical activity from traumatic loading of joints can lead to excessive loading of collagen fibres in MSK tissues leading to their failure and loss of tissue function. Common end stages of collagen fibre breakdown are preceded by matrix changes which may predispose MSK tissues to enzymatic and mechanical damage. One such change is an increased degradation of a family of small leucine-rich proteoglycans (SLRPs) which modulate the diameter, strength and assembly of collagen fibrils and bind and modify the effects of reparative growth factors and degradative cytokines within connective tissues. Altered synthesis of SLRPs and SLRP fragments have been identified in abnormal intervertebral disc, cartilage and tendon. Very little is known however about how these fragments are generated within these tissues and how they affect growth factor binding or collagen fibril formation. This deficiency will be addressed in our proposed study which will provide novel information on mechanisms of cartilage, intervertebral disc and tendon degeneration and potential therapeutic and diagnostic targets which may be exploited in future studies on the treatment of these musculoskeletal conditions.Read moreRead less
Identifying A Novel Aggrecanase In Mouse Cartilage
Funder
National Health and Medical Research Council
Funding Amount
$299,227.00
Summary
Destructive enzymes degrade cartilage in arthritis. Aggrecan is a major structural molecule that gives cartilage its cushioning properties, and aggrecan is also destroyed by harmful enzymes in arthritis. We have discovered a new enzyme that degrades aggrecan. This project aims to identify and study this new enzyme, and to determine its role in aggrecan degradation.
I am a cartilage biochemist investigating (1) cartilage remodelling in normal skeletal growth & development and (2) the molecular events that destroy cartilage in arthritic diseases. My research focuses on the molecules that define cartilage structure, and the enzymes that degrade and remodel it. Our analyses include work with molecules in test tubes, genetically modified mice with degradation-resistant cartilage, and synovial fluid samples from arthritis patients.