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
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 Design, Development And Clinical Assessment Of A New Metacarpophalangeal Joint Prosthesis
Funder
National Health and Medical Research Council
Funding Amount
$188,450.00
Summary
Rheumatoid arthritis is a crippling form of arthritis that affects many people in the community. It commonly involves the finger joints in the hands resulting in deformity, pain and subsequent loss of function. There have been implants designed for finger joint replacement, but unfortunately these implants have had only moderate benefits and can break and lead to further joint destruction resulting in the worsening of deformity and pain. A new implant for finger joint replacement has been develo ....Rheumatoid arthritis is a crippling form of arthritis that affects many people in the community. It commonly involves the finger joints in the hands resulting in deformity, pain and subsequent loss of function. There have been implants designed for finger joint replacement, but unfortunately these implants have had only moderate benefits and can break and lead to further joint destruction resulting in the worsening of deformity and pain. A new implant for finger joint replacement has been developed. This implant has several potential advantages. Firstly the unique design acts to prevent recurring deformity in the fingers with rheumatoid disease while allowing functional motion. Secondly, it is thought that patients will return to function earlier and avoid the need for further finger surgery as this implant design relies less on the tissues around it for stability. The purpose of this study is to investigate the biomechanical and clinical benefits of this new implant for finger joint replacement. The new design will undergo specific laboratory tests and be used in a clinical trial to quantify the therapeutic benefits it provides to patients with rheumatoid arthritis.Read moreRead less
Translation Of Effective Interventions In Injury Prevention And Trauma Care To A Chinese Setting
Funder
National Health and Medical Research Council
Funding Amount
$349,407.00
Summary
Evidence informed injury policy is not currently well developed in China. This research project will provide measures of the effectiveness of both a trauma care protocol in a hospital setting, and an intervention program for novice driver education-training in China, and will therefore contribute to the building of an evidence based injury prevention capacity in China.