Cartilage Destruction In Arthritis: Mechanism Of Aggrecanase And Matrix Metalloproteinase Action In Vivo And In Vitro
Funder
National Health and Medical Research Council
Funding Amount
$703,180.00
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 ....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.Read moreRead less
Functional Effects Of Antibodies To Collagen On Cartilage Synthesis And Degradation
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies ar ....It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies are disease-associated. There may be particular regions on the collagen molecule where antibody-binding causes damage. This project is based on the hypothesis that antibodies to collagen type II, which transfer arthritis in mice, are those that react specifically with regions of the collagen fibrils that are crucial for cartilage stability and function. We plan to test this hypothesis in an in vitro system using cultured cartilage. We predict, based on our preliminary data, that antibodies to collagen II from mice with CIA will interfere with the normal assembly and structure of cartilage. We will test this by adding antibodies under precisely defined conditions to cultured cartilage, and analysing the matrix that is synthesised. The study would then be extended to RA with a comparison of the regions of collagen II that react with antibodies of mouse and human origin. Showing that antibodies to collagen II are directly destructive, allowing for an understanding of their site and mode of action, would greatly advance our understanding of the cause of RA and would lead to more effective forms of treatment.Read moreRead less
The Role Of Tenascin-C In Bone And Joint Pathology
Funder
National Health and Medical Research Council
Funding Amount
$215,773.00
Summary
Many diseases of bones (e.g.osteoporosis) and joints (e.g. arthritis) result from the abnormal function of cells in these tissues. Factors regulating cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. Tenascin-C is a protein produced by bone and joint cells. The role of tenascin-C in the function of bone-forming cells (osteoblasts) and bone-resorbing cells (osteoclasts) will be investigated. We will investigate whether ten ....Many diseases of bones (e.g.osteoporosis) and joints (e.g. arthritis) result from the abnormal function of cells in these tissues. Factors regulating cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. Tenascin-C is a protein produced by bone and joint cells. The role of tenascin-C in the function of bone-forming cells (osteoblasts) and bone-resorbing cells (osteoclasts) will be investigated. We will investigate whether tenascin-C is required for the bone loss that occurs in female mice when oestrogen is not present. We will also determine the role played by tenascin-C in development and recovery from arthritis. This study will contribute to the understanding of how bone and joint cells function in health and disease.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.
A Controlled Longitudinal Study Of Knee Cartilage Volume If The Offspring Of Subjects With Osteoarthritis Of The Knee.
Funder
National Health and Medical Research Council
Funding Amount
$144,392.00
Summary
Osteoarthritis is the most common cause of musculoskeletal disability and cost in Australia. Both genetic and environmental factors have been implicated as causes of this disease. As yet, however, there are no proven strategies for prevention of this very common condition and treatment of established disease is unsatisfactory. Part of the reason for this is the fact that there is no sensitive and accurate measure of early disease. In this study, we plan to evaluate knee cartilage volume assessed ....Osteoarthritis is the most common cause of musculoskeletal disability and cost in Australia. Both genetic and environmental factors have been implicated as causes of this disease. As yet, however, there are no proven strategies for prevention of this very common condition and treatment of established disease is unsatisfactory. Part of the reason for this is the fact that there is no sensitive and accurate measure of early disease. In this study, we plan to evaluate knee cartilage volume assessed by magnetic resonance imaging. This is a promising new candidate which is both accurate and sensitive. We will be measuring knee volume both cross-sectionally and longitudinally in the offspring of patients who have had knee replacement for osteoarthritis and comparing them to randomly selected controls to see if knee volume can be utilised as a marker of early or asymptomatic disease particularly in identifying which treatments may be effective at preventing osteoarthritis in later life.Read moreRead less
A Longitudinal Study Of Knee Osteoarthritis Using X-ray And Magnetic Resonance Imaging
Funder
National Health and Medical Research Council
Funding Amount
$861,925.00
Summary
Osteoarthritis is the most common form of arthritis and commonly affects the hand hip and knee in older Australians with an annual cost of around 4 billion dollars. This study will lead to a greater understanding of the role of factors influencing the development and progression of osteoarthritis of the knee by utilising a novel magnetic resonance imaging technique. In particular, it will focus on the role of physical activity and bone underlying the cartilage. If associations are discovered, ac ....Osteoarthritis is the most common form of arthritis and commonly affects the hand hip and knee in older Australians with an annual cost of around 4 billion dollars. This study will lead to a greater understanding of the role of factors influencing the development and progression of osteoarthritis of the knee by utilising a novel magnetic resonance imaging technique. In particular, it will focus on the role of physical activity and bone underlying the cartilage. If associations are discovered, accurate public health messages regarding prevention can then be developed.Read moreRead less
Modulation Of Osteoclast Formation And Function To Prevent Joint Destruction In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$443,250.00
Summary
Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may ....Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may be that while research has mainly focused on inflammation, far less is known about the processes responsible for bone damage. Normally, specialised bone cells called osteoclasts carry out bone breakdown during growth and maintenance of the skeleton. In rheumatoid arthritis, these cells are responsible for the joint damage; this proposal, therefore, focuses on inhibiting the activity of these cells as a new therapy. So far, our work using a model of human rheumatoid arthritis has demonstrated that it is possible to separate joint inflammation from joint damage by selectively targeting osteoclasts with an inhibitor known as Osteoprotegerin. Besides Osteoprotegerin, we have identified two novel molecules named OCIL and sFRP-1 and shown that they are present in the joints of animals and humans with arthritis. Very recent experiments in our laboratory show that in the test tube, OCIL and sFRP-1 (like Osteoprotegerin) block osteoclast activity. The sFRP-1 molecule may also block a very important messenger molecule in arthritis called tumour necrosis factor. We therefore propose to study the effect of OCIL and sFRP-1 in the joints of mice with arthritis. We expect that these new inhibitors will have favorable effects on joint damage. If so, they could undergo further testing for use in humans. We believe that investigations along these lines may provide a rationale for an entirely new treatment approach to improve the long term outcome for patients with arthritis.Read moreRead less
Does Childhood Physical Activity, Fitness And Fatness Impact On Knee Structural Change 20 Years Later?
Funder
National Health and Medical Research Council
Funding Amount
$301,977.00
Summary
Interventions to increase participation of physical activity (PA) and to reduce obesity in childhood are advocated to reduce the risks of cardiovascular and other diseases in adulthood, but the associations of childhood PA and obesity with knee osteoarthritic changes in adulthood are unknown. This study, with follow-up of a large cohort of Australian children over 20 years, will be the first to determine these associations using the powerful technique of magnetic resonance imaging.
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
The Role Of The Plasminogen Activators (PAs), Urokinase-PA And Tissue-type PA In Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Intra-articular fibrin deposition is an early and persistent hallmark of inflammatory responses, resulting from an altered balance between coagulation (the production of fibrin) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can have adverse effects in RA, including mediating and-or enhancing inflammation, and contributing to subsequent joint damage. The plasminogen activators (PA), urokinase PA ( ....Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Intra-articular fibrin deposition is an early and persistent hallmark of inflammatory responses, resulting from an altered balance between coagulation (the production of fibrin) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can have adverse effects in RA, including mediating and-or enhancing inflammation, and contributing to subsequent joint damage. The plasminogen activators (PA), urokinase PA (u-PA) and tissue-type PA (t-PA) convert plasminogen into plasmin which can then breakdown the accumulated fibrin. Their presence in RA patients would therefore be beneficial. However, u-PA is also implicated in cell migration leading to inflammatory cells accumulating in the joint, and cartilage destruction, both of which are detrimental to disease outcome. In the joints of RA patients there are high levels of u-PA and low levels of t-PA. We, and our collaborators, have found that in the absence of t-PA, disease is exacerbated, whilst in the absence of u-PA, the outcome depends on the type of disease, either exacerbating or ameliorating disease. This highlights the different roles u-PA can have. The current proposal aims to determine the role of u-PA in inflammation and arthritis, and whether enhancing t-PA can have beneficial outcomes with respect to disease severity. In addition, we will also study whether intra-articular fibrin deposition can, in fact, drive the inflammatory reaction and cartilage destruction seen in RA. The findings will be important for our understanding of the role of fibrin accumulation in the inflammatory and destructive processes that occur in RA, and the roles of u-PA and t-PA in enhancing and preventing them respectively. Information gained will provide clues for useful strategies for the treatment of human inflammatory diseases, including RA.Read moreRead less