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
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
The Prognostic Significance Of Obesity In Joint Arthroplasty
Funder
National Health and Medical Research Council
Funding Amount
$57,803.00
Summary
There are over 55,000 hip and knee joint replacements performed in Australia every year and the number is rising. The incidence of obesity is also rising. Higher risk of surgical complications following joint replacement surgery has been reported in obese patients. It is therefore imperative that we determine the impact obesity has on the outcome of joint replacement surgery in order to determine if treatment needs to be modified.
Relationship Of The Anabolic And Catabolic Responses In Healing A Critical Sized Defect In Rats
Funder
National Health and Medical Research Council
Funding Amount
$329,750.00
Summary
Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bon ....Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bone resorbing response, the catabolic response, may be too high and prevent healing from occurring. In normal bone healing, there is a balance between the anabolic and catabolic response. In disordered bone healing, these responses are out of balance. Several reasonably new treatments are available which can increase the anabolic response or decrease the catabolic response. We have preliminary results showing that with these agents we can bring these elements into better control, and thus drive bone healing. We have optimised an animal model where both the anabolic and catabolic responses can be controlled. In this project, we explore the optimisation of the timing and magnitude of anabolic and catabolic responses in bone healing.Read moreRead less
Prevention And Treatment Of Bone Infection With CSA-90
Funder
National Health and Medical Research Council
Funding Amount
$350,983.00
Summary
Bone infections are a major challenge to treat, especially with the rise of drug resistant “superbugs”. We have access to a new agent, CSA-90, that has dual properties of being anti-microbial (antibiotic) and helps encourage bone growth. This project aims to expand upon our prior research and test CSA-90 for the treatment of chronic bone infections. We will also look at applying this technology to joint replacements and this drug may be particularly useful for coating orthopaedic implants.
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
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