Investigation And Modulation Of RANKL-induced Osteoclastogensis, Bone Resorption And Signaling Pathways
Funder
National Health and Medical Research Council
Funding Amount
$33,825.00
Summary
Osteoclasts are exclusively responsible for the degradation of bone matrix. RANKL is a member of a ligand-receptor system which directly regulates osteoclast differentiation and bone resorption. New treatment regime for various bone diseases have been highly sought after for many years. The identification of potential natural compounds that inhibit the formation and function of osteoclasts might serve as a useful tool for such treatment.
NT-3 As An Upstream And Potentially Master Regulator Promoting Bone Fracture Healing
Funder
National Health and Medical Research Council
Funding Amount
$712,857.00
Summary
There is a strong clinical need for cost-effective treatments for delayed healing or non-union bone fractures. Our recent data suggest injury site-derived neurotrophin-3 (NT-3) may be an important overall regulator of bone repair by inducing key factors involved in fracture callus formation and remodelling. This project will address roles and mechanisms of endogenous NT-3 in bone repair and the likelihood of exogenous NT-3 protein in promoting bone healing in clinically relevant fracture models.
Fractures And Bisphosphonates: Reviving Osteoporosis Treatment Uptake By Identifying The Genetic, Material, And Microstructural Risk Factors Of Atypical Femur Fractures.
Funder
National Health and Medical Research Council
Funding Amount
$1,053,094.00
Summary
Atypical femoral fractures (AFF) are uncommon, but catastrophic, complications of antiresorptive osteoporosis treatments including bisphosphonates. We will identify patients at risk of AFF by determining changes in their bone structure and quality, and identifying genes that increase the risk of these fractures. In this way, cheap and effective antiresorptive treatments can be targeted to patients at the lowest risk of AFF and alternative treatments to those at highest risk.
Heat Shock Transcription Factors In Bone Remodeling And Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,427.00
Summary
The denisity of bone is finely balaned and required for a healthy lifestyle. During times of disease, damage or drug treatments the bone can be compromised, often decreasing in density and becoming fragile. This often leads to fractures, pain and a poor quality of life. This proposal seeks to investigate whether stress insults to bones plays a role in the loss of bone. This will provide new insights into bone loss during disease and lead to novel treatment strategies.
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
Centre For Research Excellence In Total Joint Replacement OPtimising OUtcomes, Equity, Cost Effectiveness And Patient Selection (OPUS)
Funder
National Health and Medical Research Council
Funding Amount
$2,500,000.00
Summary
Joint replacement surgery is one of the most successful surgeries performed in Australia and globally. With an ageing population, demand for this procedure will increase dramatically, placing burden on a constrained health system. This Centre targets the journey of patients undergoing joint replacement surgery, seeking to optimise patient safety and outcomes, in addition to improving efficiencies and equitablity of this important surgical procedure.
Maximum Acceptable Risk Of Complication In Total Knee Arthroplasty (MARKA) Study: Using Discreet Choice Experiments To Elicit Patient And Surgeon Perception Of Acceptable Risk In Total Knee Arthroplasty
Funder
National Health and Medical Research Council
Funding Amount
$465,199.00
Summary
Patient expectation is the strongest predictor of satisfaction following total knee replacement. Dissatisfaction with surgery is reported in approximately 1 in 5 patients undergoing knee replacement. Unrealistic patient expectations and uninformed perceptions of potential benefits, risks and limitations of surgery lead to dissatisfaction in many cases. This study will examine the “risk-benefit” preferences in patients and surgeons considering total knee replacement as a treatment option for end- ....Patient expectation is the strongest predictor of satisfaction following total knee replacement. Dissatisfaction with surgery is reported in approximately 1 in 5 patients undergoing knee replacement. Unrealistic patient expectations and uninformed perceptions of potential benefits, risks and limitations of surgery lead to dissatisfaction in many cases. This study will examine the “risk-benefit” preferences in patients and surgeons considering total knee replacement as a treatment option for end-stage osteoarthritis.Read moreRead less
The Role Of TNF Family Members TWEAK And TNF-alpha In Bone Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$566,946.00
Summary
Bone remodelling, or turnover, is the process by which bone is broken down by osteoclasts and replaced by osteoblasts. Disruption of this process is the cause of many bone-related diseases that affect millions of Australians and countless others worldwide. It is controlled by the complex interactions of a large number of systemic factors (hormones) and locally acting agents, such as chemokines and cytokines, the details of which are not fully understood. Each of these factors, however, is a pote ....Bone remodelling, or turnover, is the process by which bone is broken down by osteoclasts and replaced by osteoblasts. Disruption of this process is the cause of many bone-related diseases that affect millions of Australians and countless others worldwide. It is controlled by the complex interactions of a large number of systemic factors (hormones) and locally acting agents, such as chemokines and cytokines, the details of which are not fully understood. Each of these factors, however, is a potential therapeutic target. Pro-inflammatory cytokines, those that are associated with inflammatory diseases such as Rheumatoid Arthritis (RA), are known to have key roles in both the physiology and pathology of bone. TWEAK is a recently described member of the TNF family of cytokines. We have shown that TWEAK is a novel mediator of inflammatory arthritis in mouse model systems and is therefore a likely candidate as a therapeutic target. We now have extensive preliminary data to suggest that TWEAK is involved in human RA, and also in the regulation of normal bone remodelling. TWEAK therefore may be implicated in a wide spread of bone diseases, including osteoporosis. We believe it is of great importance to perform a thorough analysis of TWEAK in bone biology, and we propose to do so.Read moreRead less
Structural And Functional Analyses Of Rat Receptor Activator Of NF-kb Ligand
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fra ....Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. This proposal addresses the important and fundamental issue of RANKL regarding the role of molecular structure on its biological function. We have established that the TNF-like core domain is the functional domain, important for osteoclastogenesis, osteoclast polarisation and protecting against Fas-triggered apoptosis. This proposal will further characterise the mutant forms of the TNF-like core domain of RANKL using site directed mutagenesis and protein truncation analysis, and assess their respective binding activities to OPG and RANK, and their biological activities both in vitro and in vivo. It will lead us into better understanding of the structure-function relationship of RANKL. Ideally, we would like to develop a relative agent for the suppression of osteolysis in orthopaedic related diseases including osteoporosis. Such an optimized molecule could become a potent therapeutic agent that selectively inhibits osteoclast formation and bone resorption.Read moreRead less