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
Bone-specific Sclerostin And SIBLING Proteins In Osteoarthritis: Novel Contributions To Cartilage And Bone Pathology
Funder
National Health and Medical Research Council
Funding Amount
$441,058.00
Summary
Arthritis is a major clinical problem and involves the destruction of cartilage in joints. However, the mechanisms of how this cartilage destruction is initiated and progresses remain poorly understood. We recently discovered that that three proteins that play a role in bone are also produced in cartilage and are increased in cartilage during osteoarthritis. We will determine the role of each of these in the disease mechanism to provide new therapeutic and biomarker targets.
Molecular Mechanisms Of Cartilage Degeneration In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$457,517.00
Summary
Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the mo ....Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the molecular changes and pathways involved in both the onset and progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and the pathways involved in the onset of this disease process can be discovered. However, to investigate changes at the initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear mRNA amplification methods to overcome inherent problems with tissue availability from this small animal species. Successful completion of these studies will for the first time allow identification of the complex changes that occur in early OA. An important and likely outcome of this research will be identification of novel matrix proteins and regulatory molecules that will provide critical information for the development of new diagnostic and therapeutic approaches to OA.Read moreRead less
In Australia osteoarthritis is the leading cause of pain and disability with the majority of individuals displaying radiographic evidence of this condition by age 65. We are developing two novel technologies which use patients' own stem cells to repair damaged cartilage. This project involves both the advancement of these technologies as well as their evaluation using a sheep cartilage repair model. These technologies offer significant promise for those suffering joint pain.
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
The Role Of A Novel Extracellular Matrix Protein, WARP, In Cartilage Development, Function And Pathology
Funder
National Health and Medical Research Council
Funding Amount
$482,500.00
Summary
The environment outside all cells is absolutely essential for normal growth and development. In order to undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the various extracellular matrix components and how they interact to form a functional extracellular matrix. We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-domain-related protein. Our experiments demonstrate that WARP is ....The environment outside all cells is absolutely essential for normal growth and development. In order to undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the various extracellular matrix components and how they interact to form a functional extracellular matrix. We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-domain-related protein. Our experiments demonstrate that WARP is an important constituent of the three-dimensional structure of the extracellular matrix of the articular surface of cartilage. We can show that WARP forms large-scale structures in tissue culture experiments and in extracts from mouse cartilage, and we have some new data which suggests that WARP interacts specifically with collagen II, a large and quantitatively major component of cartilage. We will explore the function of WARP in cartilage and include in vitro experiments that will reveal information about its distribution, tissue forms, and interactions with other extracellular matrix components (PART 1). To define the in vivo role of WARP we will generate a WARP gene knockout mouse (PART 2). These experiments will provide valuable information about the structure of the cartilage in the joint on the surface of bone and in particular the function of WARP in this structure. Since WARP is at the articular cartilage surface we asked whether WARP is lost in cartilage degeneration. In cartilage tissue grown in vitro under conditions that promote cartilage degradation, WARP is fragmented and released from the cartilage surface. We will explore this further in in vitro and in vivo models of cartilage breakdown (PART 3). Thus, in addition to promoting a new understanding of cartilage structure WARP has the exciting potential to become a specific biomarker for arthritis a major joint degenerative disease with high medical and financial cost to the community.Read moreRead less
A Long Term Follow-up Of The Offspring Cohort: A Controlled Study Of Those At Higher Risk Of Knee Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$238,168.00
Summary
Osteoarthritis is the most common musculoskeletal disorder. Despite this, relatively little is known about how the disease develops. This study will use a powerful technique known as MRI scanning to determine the sequence of changes over 10 years in subjects at higher risk of osteoarthritis (based on their family history) but who do not yet have established disease on radiographs (even though many have symptoms).
Factors That Affect Knee Structure In Healthy Women
Funder
National Health and Medical Research Council
Funding Amount
$199,176.00
Summary
Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life, affecting women more often than men. The importance of OA has been acknowledged by its listing within musculoskeletal disease, the 7th health priority in Australia. It is 4 times as common in women as in men.Treatments which slow or prevent OA progressing are limited, so prevention must play a key role. With increasing disease severity, joint cartilage is lost. We have recently developed a ....Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life, affecting women more often than men. The importance of OA has been acknowledged by its listing within musculoskeletal disease, the 7th health priority in Australia. It is 4 times as common in women as in men.Treatments which slow or prevent OA progressing are limited, so prevention must play a key role. With increasing disease severity, joint cartilage is lost. We have recently developed a method to measure joint cartilage from magnetic resonance imaging (MRI) scans which is able to assess the severity of structural changes in the knee. Using this method will allow us to assess 2 issues: 1) Obesity is the only identified modifiable risk factor for knee OA. However, the mechanism is poorly understood. Weight loss programs may be more effective at reducing the risk of OA if they are combined with programs aimed at maintaining muscle mass. 2) Bone is important in development of Knee OA, but its role is poorly understood. Understanding how bone metabolism relates to risk of knee OA may allow us to prevent disease. Bone is more likely to respond to pharmacological manipulation than cartilage. Thus it may prove a more effective target for intervention than cartilage. The Geelong Osteoporosis Study was begun in 1994 to study bone health in Australian women (urban and rural). Much information relevant to the risk of OA has been collected over the past decade. By performing MRI of the knee now and in 2 years time, we will determine the effect of different measures of obesity and bone metabolism on structural change at the knee which predisposes to OA. Since both of these factors (obesity and bone metabolism) are potentially modifiable, this study may offer new avenues of prevention and therapy in knee OA. This has the potential to promote a better quality of life as people age and to reduce the economic burden of knee OA in the community.Read moreRead less
Does Vitamin D Supplementation Prevent Progression Of Knee Osteoarthritis? A Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$1,016,758.00
Summary
Observational evidence suggests that vitamin D deficiency may have a role in the causes of osteoarthritis (OA) and there are biologically plausible mechanisms to explain this. There is, however, no evidence which shows that intervening with vitamin D supplementation can slow the progression of OA. This study will compare knee OA structural changes in patients receiving vitamin D supplementation with those receiving a placebo. Use of MRI will provide sensitive measures of knee OA changes.
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