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.
Chemokines are small molecules that are released by a number of cell types, particularly monocytes, when inflammation occurs. Chronic inflammatory disease is associated with severe bone erosion and loss of bone quality. Surprisingly, chemokines control osteoclast development as well as macrophage activation; even if the osteoclast has formed, blocking chemokine signalling prevents bone resorption. Chemokines are a new and exciting target to control osteoclast formation.
Common Pathways Influencing Osteoporosis And Atherosclerosis Clinical Risk
Funder
National Health and Medical Research Council
Funding Amount
$443,090.00
Summary
It is recognised there are strong inherited effects on bone density and bone turnover as well as cardiovascular markers like serum cholesterol and arterial function. The study will examine the relationship between osteoporosis and atherosclerosis risk using the powerful twin model and two established large twin cohorts in Sydney and Melbourne. The work may lead to better prediction of common risk factors for these two important conditions.
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
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
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
An Evaluation Of Bone Density Screening In Premenopausal Women
Funder
National Health and Medical Research Council
Funding Amount
$175,046.00
Summary
Fractures due to osteoporosis are a major public health problem. Bone density is one of the major predictors of these osteoporotic fractures and is the result of the amount of bone gained in early life (i.e peak bone mass) and subsequent bone loss. Cigarette smoking, physical inactivity and inadequate calcium intake are widely regarded as risk factors for osteoporosis (as well as for other common diseases). Despite this information being widely available and actively promoted, the prevalence of ....Fractures due to osteoporosis are a major public health problem. Bone density is one of the major predictors of these osteoporotic fractures and is the result of the amount of bone gained in early life (i.e peak bone mass) and subsequent bone loss. Cigarette smoking, physical inactivity and inadequate calcium intake are widely regarded as risk factors for osteoporosis (as well as for other common diseases). Despite this information being widely available and actively promoted, the prevalence of these risk factors in the population remains unacceptably high suggesting that education alone at the public health level is not sufficient to modify these behaviours. In women (mean age 33) taking part in a study of the determinants of bone mass in children, we recently reported substantial change in these behaviours at 12 months follow-up when women received an information leaflet and individualised bone density information. These women were highly selected and it is unclear if this response is representative of all women. The aims of this study are, therefore, to test hypotheses in a random electoral roll sample of 400 women aged 25-44 from metropolitan Hobart relating to the effect of different types of educational programs and low initial bone mass on both lifestyle changes and changes in bone density over two years. This study will lead to accurate information about how best to target osteoporosis prevention programs in the younger age groups. Furthermore, as risk factors for cardiovascular and other diseases are often similar to those for osteoporosis, it is likely to provide insights into the prevention of these diseases and, as a result, have much greater potential for decreasing disease in the community.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.