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
Improving Translation Of Evidence Into Practice For Musculoskeletal Conditions
Funder
National Health and Medical Research Council
Funding Amount
$948,684.00
Summary
Musculoskeletal conditions place a huge burden on the world’s population. Yet current trials in this field may not reflect priorities based upon this burden and few trials address well-recognised evidence-practice gaps. My fellowship will aim to transform the current ad hoc approach to Australian musculoskeletal clinical trials. It will identify the most critical unanswered questions, formulate a national research agenda, and identify best methods for optimising uptake of findings into practice.
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.
Functional Variants Of RUNX2 Related To Bone Density
Funder
National Health and Medical Research Council
Funding Amount
$451,938.00
Summary
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ....Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ancestral form of this gene. We now need to know how this change in this promoter alters bone density and we are following up on observations that other important transcription factors bind to the variable site in the promoter. Furthermore, we have assembled a large collection of samples from people who have had extensive measures of bone density and arthritis in order to accurately measure the impact of this gene on bone density, osteoarthritis and bone fracture. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. Such mutations in a region called the Q-repeat are rather common, 1-200 people are carriers. Our data show that these mutant proteins are not as efficient at their task of regulating other genes. We now want to know how this occurs in a molecular sense, since it is known that the Runx2 protein resides in the nucleus of the cell and interacts with many other regulators. This part of the project is being done with one of the world experts on gene regulation in bone cells. Since RUNX2 is a master regulator of the cells that make bone, this gives hope that it may be possible to alter bone formation through this master regulator.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE130100771
Funder
Australian Research Council
Funding Amount
$278,780.00
Summary
Automated system for bone texture analysis of osteoarthritis in hand radiographs. Early detection and prediction of hand osteoarthritis are not feasible by current methods of visual grading of hand radiographs. This project will develop a novel, fully automated system for selection of bone texture regions on hand radiographs and their analysis to address this problem.
The Neuromuscular And Biomechanical Gait Risk Factors For Progression Of Hip Ostoearthritis.
Funder
National Health and Medical Research Council
Funding Amount
$91,367.00
Summary
Hip osteoarthritis (OA) is a common condition in older adults and it is often associated with pain, stiffness and functional limitations particularly in walking. There is no cure for hip OA and the end result is often a total hip replacement. Knowledge of neuromuscular and biomechanical characteristics of hip OA during walking and any relationships to disease progression will provide a better understanding of risk factors for progression of hip OA. This knowledge may guide future hip OA manageme ....Hip osteoarthritis (OA) is a common condition in older adults and it is often associated with pain, stiffness and functional limitations particularly in walking. There is no cure for hip OA and the end result is often a total hip replacement. Knowledge of neuromuscular and biomechanical characteristics of hip OA during walking and any relationships to disease progression will provide a better understanding of risk factors for progression of hip OA. This knowledge may guide future hip OA management plans to slow the progression of the disease.Read moreRead less
Ankylosing spondylitis (AS) is a chronic arthritis which causes severe back and joint pain in young men and women. It can be difficult to diagnose as it takes years to show up on x-ray, and by then the joints are already damaged. This study looks at new ways to diagnose people with AS much earlier, which will allow earlier treatment and better outcomes. The study will also look at the role of lifestyle factors such as diet and physical activity which might impact on AS.
Program evaluation of the osteoarthritis awareness hub. Persons with osteoarthritis generally have poor knowledge about their disease and its appropriate management. The aim of this project is to evaluate whether improved knowledge, and management decisions of persons with osteoarthritis, can ultimately lead to improved health outcomes.
DICKENS - A Randomised Controlled Trial Of DIaCerein To Treat KneE Osteoarthritis With EffusioN-Synovitis
Funder
National Health and Medical Research Council
Funding Amount
$1,327,836.00
Summary
Knee osteoarthritis (OA) is common, but the current treatments are poor. Almost 60% of people with knee OA have joint inflammation. Patients with inflammation are more likely to experience joint pain and rapid joint destruction. We propose that treating patients with inflammatory knee OA with the anti-inflammatory drug, diacerein, will reduce pain and joint damage.
Does Statin Use Have A Disease Modifying Effect In Symptomatic Knee Osteoarthritis?
Funder
National Health and Medical Research Council
Funding Amount
$133,194.00
Summary
Osteoarthritis (OA) is a major cause of knee pain and disability. Treatments are limited to reducing pain and improving function: no therapy slows disease progression, with symptomatic end-stage OA treated by knee replacement. Statins, a drug class used to lower cholesterol levels, may affect the structural progression in knee OA. We propose a randomised controlled trial to see if statin use slows the progression of knee OA, which would delay or prevent the need for joint replacement.