Proteomics Of Arthritis: Exploring Mechanisms Of Cartilage Degradation And Biomarker Identification
Funder
National Health and Medical Research Council
Funding Amount
$592,034.00
Summary
Arthritis is a major clinical and socio-economic problem. Arthritis involves the destruction of cartilage in joints. However, the mechanisms of initiation and progression of cartilage destruction remain poorly understood. Our studies will use new proteomic approaches to identify the changes in protein synthesis and degradation in mouse models of arthritis. This will provide critical information on disease mechanisms and for the development of diagnostic biomarkers and therapeutic approaches
Novel Roles For IL-33 In The Maintenance Of Bone Mass And As A Locally Derived Anabolic Factor For Bone
Funder
National Health and Medical Research Council
Funding Amount
$592,574.00
Summary
Over 10% of the population have thin, brittle bones that fracture easily, and is often seen in elderly people. When diagnosed, a fracture has usually already occurred and the bone is already thin. Drugs are available to stop further bone weakening, but building new bone would be best. We have found a protein in bone that reduces bone loss and stimulates bone formation processes. This project seeks to determine how this protein works and how to exploit it to design new bone building therapies.
Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better i ....Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better investigate the mechanisms of the bone loss. Drugs to stop the loss of bone have only recently been available to patients and many new treatments are being developed. While most of these drugs are proving useful to treat osteoporosis, their suitability for the treatment of bone loss in diseases such as periodontal disease, rheumatoid arthritis and peri-implant osteolysis is largely unknown. As the way bone is lost in these inflammatory diseases quite different from osteoporosis different treatments are needed. This project aims to better understand bone loss in these diseases and identify new treatments to prevent the debilitating bone loss associated with inflammation in disease.Read moreRead less
Effect Of Lipid Mediators And Dietary Fats In Bone Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$380,250.00
Summary
Osteoporosis in a major public health problem which directly affects about 10% of the population, which is currently around 2 million Australians. With aging of the population, it is projected that this proportion will increase to more than 13% over the next 20 years. When it is considered that the direct hospital and residential care costs attributable to osteoporotic fractures currently approaches $2 billion per annum, low-cost interventions for increasing bone strength which are easily applie ....Osteoporosis in a major public health problem which directly affects about 10% of the population, which is currently around 2 million Australians. With aging of the population, it is projected that this proportion will increase to more than 13% over the next 20 years. When it is considered that the direct hospital and residential care costs attributable to osteoporotic fractures currently approaches $2 billion per annum, low-cost interventions for increasing bone strength which are easily applied to the elderly population have enormous potential for health benefits in Australia. Thus study will examine the effects of dietary omega-3 fats, of the kind found in fish and fish oil, on the biology of bone metabolism and on bone strength. The results will provide information which may be used in developing simple drug or dietary strategies for large-scale use for increasing bone mass and strength in the elderly population. A strength of the study arises from the combination of research expertise in (a) dietary fats, and (b) molecular biology of bone cells, and (c) animal models of bone metabolism which are amenable to dietary interventions. This combination is unique, but builds on well established systems which hitherto have existed in separate research paradigms. The Chief Investigator has considerable experience in development of diets enriched in omega-3 fats which are practical and suitable for daily use on a long-term basis. This adds considerably to the potential significance of the outcomes because, if favourable effects of omega-3 fats are observed and are characterised with regard to mechanisms, the results can be rapidly translated into large-scale clinical use.Read moreRead less
The Role Of TNF Family Members TWEAK And TNF-alpha In Bone Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$566,946.00
Summary
Bone remodelling, or turnover, is the process by which bone is broken down by osteoclasts and replaced by osteoblasts. Disruption of this process is the cause of many bone-related diseases that affect millions of Australians and countless others worldwide. It is controlled by the complex interactions of a large number of systemic factors (hormones) and locally acting agents, such as chemokines and cytokines, the details of which are not fully understood. Each of these factors, however, is a pote ....Bone remodelling, or turnover, is the process by which bone is broken down by osteoclasts and replaced by osteoblasts. Disruption of this process is the cause of many bone-related diseases that affect millions of Australians and countless others worldwide. It is controlled by the complex interactions of a large number of systemic factors (hormones) and locally acting agents, such as chemokines and cytokines, the details of which are not fully understood. Each of these factors, however, is a potential therapeutic target. Pro-inflammatory cytokines, those that are associated with inflammatory diseases such as Rheumatoid Arthritis (RA), are known to have key roles in both the physiology and pathology of bone. TWEAK is a recently described member of the TNF family of cytokines. We have shown that TWEAK is a novel mediator of inflammatory arthritis in mouse model systems and is therefore a likely candidate as a therapeutic target. We now have extensive preliminary data to suggest that TWEAK is involved in human RA, and also in the regulation of normal bone remodelling. TWEAK therefore may be implicated in a wide spread of bone diseases, including osteoporosis. We believe it is of great importance to perform a thorough analysis of TWEAK in bone biology, and we propose to do so.Read moreRead less
Cartilage Destruction In Joint Disease: Studies With ADAMTS-4 And ADAMTS-5 Deficient Mice
Funder
National Health and Medical Research Council
Funding Amount
$540,600.00
Summary
In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that ADAMTS-4 and-or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate mice containing mutant ADAMTS-4 and-or -5 in all cells, or [2] in car ....In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that ADAMTS-4 and-or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate mice containing mutant ADAMTS-4 and-or -5 in all cells, or [2] in cartilage cells only. [3] Analyse mutant mice for changes in skeletal architecture, changes in ADAMTS mRNA and protein, and changes in aggrecan breakdown products. [4] Assess disease severity in mutant mice in in vivo models of joint disease. We already have mice with ADAMTS-4, or -5, mutated in all tissues and we are generating the double mutants now. We will also generate single and double mutants with dysfunctional enzymes in cartilage only. We will examine skeletal structure by histology and X-ray at all ages and monitor for expression of ADAMTS-1 and -9 to detect any compensatory over-production of other potential 'aggrecanases'. We will also do co-culture experiments in which cartilage and synovial cells from combinations of mutant and control mice will be incubated together to determine whether synovial ADAMTS can penetrate and degrade aggrecan in cartilage. Finally we will induce arthritis in mutant and control mice and monitor them to detect differences in the time of disease onset, the rate of disease progression and overall disease severity. A comparison of whole-mouse with cartilage only mutants in the in vivo models will complement the in vitro co-culture studies and determine whether other joint tissues such as synovium and joint capsule can also produce ADAMTS enzymes that destroy cartilage. This is not known. Together these experiments will reveal if, where and when ADAMTS-4 and-or -5 are active, and whether indeed they are the best targets for drug development.Read moreRead less
Economic Evaluation And Health Outcomes Of Arthritis And Its Treatments
Funder
National Health and Medical Research Council
Funding Amount
$360,660.00
Summary
Musculoskeletal diseases are the most common single cause of chronic disability in Australia and total joint replacement is rapidly becoming one of the most commonly performed operations. This burden of illness is likely to increase with our ageing population and there is an urgent need to obtain data relating to the costs and outcomes in the Australian context so that appropriate planning of health services and resources can be carried out. The WHO (World Health Organisation) has declared 2000 ....Musculoskeletal diseases are the most common single cause of chronic disability in Australia and total joint replacement is rapidly becoming one of the most commonly performed operations. This burden of illness is likely to increase with our ageing population and there is an urgent need to obtain data relating to the costs and outcomes in the Australian context so that appropriate planning of health services and resources can be carried out. The WHO (World Health Organisation) has declared 2000 to 2010 the Bone and Joint Decade, recommending that research into musculoskeletal disorders be a priority. We have been recruiting and following a unique cohort of osteoarthritis and rheumatoid arthritis patients, from both the public and private health sectors, who have been carefully documenting their health outcomes, health care costs (including primary, revision and bilateral hip and knee joint replacement surgery), out-of-pocket and indirect costs related to their arthritis. Long-term follow-up is now essential to obtain a clear picture of the impact of living with arthritis over time and the cost-effectiveness and predictors of good and bad outcomes of joint replacement surgery. The information derived from this study will be useful for patients and doctors in making their decisions about treatments, as well as for health care providers in planning of health services for arthritis sufferers. Given that the cohorts are already established, the study is in a unique position to provide ongoing important longer-term data for relatively low cost.Read moreRead less
The Role Of Suppressor Of Cytokine Signalling-3 (SOCS-3) In Chondrocytes During Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$348,392.00
Summary
Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced ....Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced by a wide range of stimuli, especially from a group called the IL-6 family. We have preliminary data showing that cartilage cells (chondrocytes) normally produce a particular SOCS protein, called SOCS-3. We have also shown that when SOCS-3 production is dysregulated, the chondrocytes undergo excessive proliferation. Normal chondrocyte function is important during skeletal development and diseases such as osteoarthritis are thought to result from abnormal chondrocyte behaviour. It is likely that SOCS-3 has a key role in regulating chondrocyte function. The aim of this proposal is therefore to examine the role of SOCS-3 in chondrocytes, during development and in disease. Much of our understanding of the role of the SOCS proteins comes from the construction of mutant mice that lack a particular SOCS protein. When mutant mice are made that lack SOCS-3 in the whole animal the mice die before birth and so virtually nothing is known about the role of SOCS-3 in chondrocytes and the implications for cartilage in disease states, such as arthritis. To answer this we will create mice that lack SOCS-3 specifically in their chondrocytes. Evaluating the role of SOCS-3 in cartilage development and chondrocyte function during degenerative and inflammatory disease states is potentially of major clinical importance in improving our understanding of arthritis and of cartilage repair.Read moreRead less
Novel Pathways Involving APC And PAR-2 In Cartilage Degradation In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$448,834.00
Summary
Loss of the cartilage that normally lines the ends of bones is central to joint failure in arthritis and the need for replacement surgery. There are presently no treatments that stop cartilage breakdown in joint disease. This project investigates the role of a new pathway not previously thought to be active in cartilage, in the progressive damage seen in arthritis. Successful completion of these studies may provide a novel new strategy to treat joint disease.