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
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
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
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.
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
Predictors Of The Outcomes For Joint Inflammation And Damage In Recent Onset Rheumatoid Arthritis Patients
Funder
National Health and Medical Research Council
Funding Amount
$255,750.00
Summary
Currently, it is difficult to predict what will happen to an individual patient who presents with newly diagnosed rheumatoid arthritis, either as a result of the natural history of the disease or as a result of drug treatment. It is also difficult to decide which drug treatment to offer a patient and when to decide to change the treatment to obtain a better clinical response. This study will investigate whether it is possible to predict the outcomes for a particular patient with rheumatoid arthr ....Currently, it is difficult to predict what will happen to an individual patient who presents with newly diagnosed rheumatoid arthritis, either as a result of the natural history of the disease or as a result of drug treatment. It is also difficult to decide which drug treatment to offer a patient and when to decide to change the treatment to obtain a better clinical response. This study will investigate whether it is possible to predict the outcomes for a particular patient with rheumatoid arthritis for joint inflammation and joint destruction, based on the findings in the joint lining tissue. This study will also investigate whether it is possible to make decisions on the likely success of drug treatment given to a patient with rheumatoid arthritis based on the initial or subsequent joint lining tissue biopsies. If successful, this study will lead to a greater ability to advise patients about likely outcomes from their condition, either with or without treatment and also to predict whether a treatment is likely to work at an early stage. In addition, this study may identify future potential treatments for rheumatoid arthritis.Read moreRead less