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
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
Skeletal disease is a major problem for children with mucopolysaccharidoses (MPS). Patients suffer from early onset osteoporosis and osteoarthritis, severely affecting their quality of life. We will evaluate a lentiviral gene therapy vector developed in-house for its capacity to transduce bone, cartilage, synovial and ligament cells in a mouse model of MPS VI. Our goal is to generate high level, sustained expression of the deficient MPS enzyme and alter the course of skeletal disease in MPS.
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
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.
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
Dissection Of The Mechanisms Of Action Of Evolutionarily Conserved Apoptotic Pathway Components
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis. The first recognised component of the mammalian cell death machi ....Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis. The first recognised component of the mammalian cell death machinery was Bcl-2; a protein associated with development of cancer. Despite much research since then, the way in which Bcl-2 and related proteins function is still unknown. This project capitalises on previous genetic and biochemical studies in a model genetic organism (the roundworm) to address this important issue. Animal cell death pathway components can be introduced into yeast such that activation of the introduced pathways leads to yeast death and its inhibition promotes yeast survival. We have used this approach to reconstitute the worm cell death pathway and a major mammalian apoptosis pathway in yeast. Yeast strains bearing these reconstituted pathways will be used to test functional equivalence of candidate mammalian proteins and their putative roundworm counterparts. The system will also be exploited to identify and characterise novel proteins that regulate cell death in mammals and worms. Understanding the way in which key molecules regulate apoptosis will assist in the development of diagnostic and therapeutic reagents for many diseases in which cell death regulation is perturbed. This project capitalises on the evolutionary conservation of apoptosis to characterise the mechanisms of action of important mammalian apoptotic regulators and to seek novel mammalian apoptotic pathway components. Proteins identified in this way are likely to be important apoptotic regulators, as our approach ensures that their functions are evolutionarily conserved.Read moreRead less
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.