A Novel Strategy For The Treatment Of Chronic Skeletal Joint Defects
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Skeletal joint injuries often heal poorly with current treatment approaches and lead to the onset of osteoarthritis. This project will produce a synthetic graft with unique properties to mimic the complex structure of joint tissues, and high bioactivity to induce optimal healing of the joint. This graft will constitute a viable alternative for the treatment of skeletal joint defects, resulting in significant healthcare benefits and improved long-term outcomes.
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.
Femoroacetabular impingement (FAI) is a common cause of hip pain characterised by extra bone formation at the hip, called a cam-deformity. FAI is thought to create hip joint damage and osteoarthritis. Our 5 year longitudinal study of people with FAI in two (Melbourne and Brisbane) sites will investigate whether factors (such as cam-deformity size, hip contact force, muscle strength and joint range) can predict hip joint damage (measured with magnetic resonance imaging) over two years.
Molecular Mechanisms Of Cartilage Degeneration In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$457,517.00
Summary
Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the mo ....Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the molecular changes and pathways involved in both the onset and progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and the pathways involved in the onset of this disease process can be discovered. However, to investigate changes at the initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear mRNA amplification methods to overcome inherent problems with tissue availability from this small animal species. Successful completion of these studies will for the first time allow identification of the complex changes that occur in early OA. An important and likely outcome of this research will be identification of novel matrix proteins and regulatory molecules that will provide critical information for the development of new diagnostic and therapeutic approaches to OA.Read moreRead less
Improving Patient Outcome Following Arthroscopic Autologous Chondrocyte Implantation
Funder
National Health and Medical Research Council
Funding Amount
$345,591.00
Summary
Autologous chondrocyte implantation (ACI) is the ‘gold standard’ for treating knee cartilage defects. Traditionally, ACI was performed through open surgery. However, ACI can now be performed through ‘keyhole’ surgery, decreasing the co-morbidity of open surgery. Furthermore, optimal patient outcome is limited by a lack of knowledge in effective post-operative rehabilitation. This project will evaluate outcomes following ACI performed through keyhole surgery, in conjunction with 'accelerated' reh ....Autologous chondrocyte implantation (ACI) is the ‘gold standard’ for treating knee cartilage defects. Traditionally, ACI was performed through open surgery. However, ACI can now be performed through ‘keyhole’ surgery, decreasing the co-morbidity of open surgery. Furthermore, optimal patient outcome is limited by a lack of knowledge in effective post-operative rehabilitation. This project will evaluate outcomes following ACI performed through keyhole surgery, in conjunction with 'accelerated' rehabilitation.Read moreRead less
Mechanisms Of Cartilage Destruction And The Effects Of Treatment In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$239,830.00
Summary
Rheumatoid arthritis occurs in 1-3% of the population. It is associated with damage to joints causing pain and dificulty with mobility. There are several treatments for rheumatoid arthritis, none of which completely prevents this damage. This study looks at joint tissue and the ways in which damage occurs. It tries to understand why treatment works in some patients and not others. By doing this, the best ways of stopping joint damage will be determined. The study will also tell us the best ways ....Rheumatoid arthritis occurs in 1-3% of the population. It is associated with damage to joints causing pain and dificulty with mobility. There are several treatments for rheumatoid arthritis, none of which completely prevents this damage. This study looks at joint tissue and the ways in which damage occurs. It tries to understand why treatment works in some patients and not others. By doing this, the best ways of stopping joint damage will be determined. The study will also tell us the best ways of looking at whether treatment is working before joint damage occurs.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
A Study To Evaluate Safety And Feasibility Of Administrating Zoledronic Acid To Children And Adolescents With Acute Lymphoblastic Leukemia And Lymphoma To Prevent Joint Complication.
Funder
National Health and Medical Research Council
Funding Amount
$16,231.00
Summary
Osteonecrosis (bone death) is a debilitating complication seen following chemotherapy for acute lymphoblastic leukemia in older children. It potentially could lead to destruction of joint, severely limiting quality of life and ultimately requiring joint replacement surgery. Currently there is no effective medical treatment to manage this. Based on our animal experiments we want to study if Zoledronic acid could prevent severe joint destruction in these children and improve their quality of life.
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.
In Australia osteoarthritis is the leading cause of pain and disability with the majority of individuals displaying radiographic evidence of this condition by age 65. We are developing two novel technologies which use patients' own stem cells to repair damaged cartilage. This project involves both the advancement of these technologies as well as their evaluation using a sheep cartilage repair model. These technologies offer significant promise for those suffering joint pain.