Molecular Mechanisms Of Joint Degeneration In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$718,273.00
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 for explore the role of a new regulator of gene expression, microRNA, in the initation and progression of osteoarthritis. This will provide important new information on disease mechanisms for the development of diagnostic biomarkers and therapies
The Neuromuscular And Biomechanical Gait Risk Factors For Progression Of Hip Ostoearthritis.
Funder
National Health and Medical Research Council
Funding Amount
$91,367.00
Summary
Hip osteoarthritis (OA) is a common condition in older adults and it is often associated with pain, stiffness and functional limitations particularly in walking. There is no cure for hip OA and the end result is often a total hip replacement. Knowledge of neuromuscular and biomechanical characteristics of hip OA during walking and any relationships to disease progression will provide a better understanding of risk factors for progression of hip OA. This knowledge may guide future hip OA manageme ....Hip osteoarthritis (OA) is a common condition in older adults and it is often associated with pain, stiffness and functional limitations particularly in walking. There is no cure for hip OA and the end result is often a total hip replacement. Knowledge of neuromuscular and biomechanical characteristics of hip OA during walking and any relationships to disease progression will provide a better understanding of risk factors for progression of hip OA. This knowledge may guide future hip OA management plans to slow the progression of the disease.Read moreRead less
Are Chondrocytes The Target Cells Of Glucocorticoid Therapy In Autoimmune Arthritis?
Funder
National Health and Medical Research Council
Funding Amount
$544,619.00
Summary
Glucocorticoids (GCs) are widely used for their potent anti-inflammatory and immunomodulatory effects due to the effects GCs on immune cells or synovial fibroblasts. Recently, we have made the exciting discovery that arthritis mice with glucocorticoid receptor knock-out in chondrocyte are completely resistant to glucocorticoid treatment. This study will identify the mechanisms underlying these hormonal effects with the aim to find new targets for efficient treatments for arthritis.
Osteoarthritis (OA) affects approximately 20% of Australians and costs billions each year in joint replacements. Therapies that halt joint destruction in OA are urgently needed. We hypothesise that the little-known gene, vanin -3, is a key regulator of OA disease pathways. Our project will map vanin-3 in the joint and reveal how much vanin-3 contributes to joint destruction in mice. We expect to find a link between vanin-3 and metabolic disorders and identify new targets for therapy.
MicroRNAs As Therapeutic Targets For Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$921,754.00
Summary
microRNAs are small cellular RNA fragments that regulate protein expression. They have been shown to be crucial regulators of normal development and are associated with many disease processes. The goal of this project is to determine the role of microRNAs in the initiation and progression of joint degeneration in osteoarthritis and test the therapeutic efficacy of targeting microRNAs as new approach to OA treatment.
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
QUANTITATIVE ASSESSMENT OF LOOSENING IN HIP ARTHROPLASTIES USING MECHANICAL VIBRATION DIAGNOSTICS
Funder
National Health and Medical Research Council
Funding Amount
$185,665.00
Summary
Recent advances and improvements made to the mechanical design of artificial joints have led to greater strength, fatigue life and wear resistance. However, this extension to the working life of joint replacements has led to patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip joint replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery because of loosening at some stage of their working life. Th ....Recent advances and improvements made to the mechanical design of artificial joints have led to greater strength, fatigue life and wear resistance. However, this extension to the working life of joint replacements has led to patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip joint replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery because of loosening at some stage of their working life. This is becoming a major concern to health services around the world since revision surgery is associated with a higher risk to the patient and costs are far greater than for the primary operation. Current diagnostic techniques using radiographic imaging are both invasive and lack diagnostic accuracy. The ability to detect joint loosening and to discriminate between the various causes of joint loosening following arthroplasty is of great importance to the success of subsequent care plans. This study will be the first in the world to assess the validity of a new diagnostic test that uses low energy mechanical vibration to quantify the degree of loosening in both components of the implanted hip joint. Once the technique has been proven it could readily be extended to evaluate the degree of fixation of other implanted prostheses used to replace the knee, ankle or joints of the upper limbs.Read moreRead less
Novel Treatment Approaches To Prevent Joint Fusion In Ankylosing Spondylitis
Funder
National Health and Medical Research Council
Funding Amount
$477,440.00
Summary
Ankylosing spondylitis (AS) is a form of arthritis targeting the spine and pelvis that causes uncontrolled bone formation resulting in complete joint fusion, severe disability and even death for which no therapies are currently available. Using a mouse model that closely replicates the human disease we will characterise the changes causing this joint fusion and identify possible new targets to develop novel treatments.
Understanding How Endogenous G-CSF Mediates Inflammatory Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$531,485.00
Summary
Rheumatoid Arthritis (RA) is a common chronic inflammatory disease which targets joints. Currently, there is no cure for RA and the available anti-rheumatic drugs have limited efficacy and frequent side effects. Progress has been made in understanding the molecular pathways which drive RA and the disease is characterised by high levels of inflammatory mediators (called cytokines). This finding has led to the development and introduction of specific cytokine inhibitors into clinical practice. The ....Rheumatoid Arthritis (RA) is a common chronic inflammatory disease which targets joints. Currently, there is no cure for RA and the available anti-rheumatic drugs have limited efficacy and frequent side effects. Progress has been made in understanding the molecular pathways which drive RA and the disease is characterised by high levels of inflammatory mediators (called cytokines). This finding has led to the development and introduction of specific cytokine inhibitors into clinical practice. These inhibitors work well for some, but not all, patients. The reason why certain RA patients fail to respond to this treatment is not clear. There is great interest in identifying new cytokines in RA and in developing more effective cytokine inhibitors. Our recent research shows that a cytokine best known for its effect on blood cell development (granulocyte-colony stimulating factor or G-CSF) also plays a major role in experimental models of RA. This discovery has led to two Australian biotechnology companies - Zenyth Therapeutics Ltd., and Murigen Therapeutics Ltd, entering into a partnership to develop G-CSF antagonists for clinical trials. However, before we can take such antagonists to the clinic, we need to conduct careful pre-clinical studies to understand the basis for our findings on G-CSF in much greater detail. This will ensure this new therapy is used in the safest and most effective way.Read moreRead less