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The Effect Of Weight Loss On The Risk Of Knee Osteoarthritis And Potential Modification By Biomechanical Factors
Funder
National Health and Medical Research Council
Funding Amount
$475,388.00
Summary
Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life. This has been acknowledged by its listing as the 7th health priority in Australia. Knee OA is the most common reason for a joint replacement, thus imposing a huge financial burden to the community. Treatments which slow-prevent OA progressioning are limited and so prevention must play a key role. Obesity is the most significant, potentially modifiable risk factor for knee OA. The combinati ....Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life. This has been acknowledged by its listing as the 7th health priority in Australia. Knee OA is the most common reason for a joint replacement, thus imposing a huge financial burden to the community. Treatments which slow-prevent OA progressioning are limited and so prevention must play a key role. Obesity is the most significant, potentially modifiable risk factor for knee OA. The combination of the current epidemic of obesity in Western countries and the aging of the population is likely to have a synergistic effect on the prevalence and incidence of knee OA. Despite the consistent relationship between obesity and OA, little work has been done on the relationship between obesity and biomechanical factors such as knee angle and muscle mass and how these may interact with obesity and weight loss in modifying the risk of knee OA. It may be that weight loss programs could be more effective at reducing the risk of OA if they are combined with programs aimed at correcting muscle weakness and malalignment. 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
Role Of Musculoskeletal Biomechanical Factors In Cartilage Loss In Those Who Undergo Partial Medial Menisectomy.
Funder
National Health and Medical Research Council
Funding Amount
$654,530.00
Summary
The novel outcomes from our project are that we will identify whether musculoskeletal-biomechanical factors that can be modified are associated with adverse cartilage changes in a subgroup of individuals with an increased risk of developing knee OA, those who have undergone an APM. The findings of this research are timely and of major international significance as there is increasing attention being paid to preventing OA rather than merely treating the signs and symptoms. Our state-of-the-art me ....The novel outcomes from our project are that we will identify whether musculoskeletal-biomechanical factors that can be modified are associated with adverse cartilage changes in a subgroup of individuals with an increased risk of developing knee OA, those who have undergone an APM. The findings of this research are timely and of major international significance as there is increasing attention being paid to preventing OA rather than merely treating the signs and symptoms. Our state-of-the-art measure of cartilage changes will allow us to detect those at risk much sooner than traditional measures using radiographs. The measures are also leading edge internationally. We chose these specific factors to investigate as there is evidence that they can be modified with appropriate interventions. For example, static joint alignment could be modified with foot orthoses [Crenshaw, 2000 #1016], muscle weakness can be addressed with strength programs and mechanical loading across the knee could be reduced via weight loss programs or techniques to alter gait patterns. Currently, formal supervised post-operative rehabilitation is not routinely prescribed following APM because it is considered a routine procedure. If our research identifies risk factors for increased cartilage loss then we will be able to develop appropriate intervention strategies for individuals following an APM. These interventions can then be formally tested as to their effectiveness in reducing adverse cartilage changes using randomised controlled trials. In particular, this could lead to changes in current post-operative clinical practice for this patient group. Ultimately, this could reduce the risk of OA in the future and the resultant personal and societal costs of this condition.Read moreRead less
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
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 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
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.