Molecular Characterization Of V-ATPase V0 Domain Subunits E1 And E2 In Osteoclast
Funder
National Health and Medical Research Council
Funding Amount
$558,909.00
Summary
Osteoporotic fractures in the elderly are often linked to increased mortality rates. Excess bone resorption is a major contributor to the onset of the disease. The proposed project focuses on the investigation of the molecular mechanisms of acid secretion that is required for the bone degradation in body. The project will examine the role of the proton pump in bone resorption and seek potential targets for the treatment of osteoporosis.
Regulation Of Key Pathways Causing Peri-implant Bone Loss.
Funder
National Health and Medical Research Council
Funding Amount
$403,639.00
Summary
The failure of bone prostheses is becoming a major health problem in our aging population. Despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is now apparent that most implants fail due to bone loss around them which leads to loosening. This project aims to obtain a better understanding of the causes of implant failure and find ways to extend the life of these implants .
Targeting The Vicious Cycle Of Cancer-induced Bone Disease With TRAIL And Bisphosphonates
Funder
National Health and Medical Research Council
Funding Amount
$443,696.00
Summary
The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly ....The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly targeting cancer cells within bone, and with no evidence of toxic side effects to normal tissues. Death receptor targeting by TRAIL, and bisphosphonates induce cancer cell apoptosis through different but overlapping signaling pathways. Therefore, combination of the two approaches may facilitate killing of tumour cells that resist death induction through either one of the pathways. Combination therapy may also reduce the probability of acquired resistance to either therapy. We propose that a combinatorial approach, using bisphosphonates to selectively target osteoclasts and TRAIL to selectively target cancer cells, would be an ideal therapeutic and safe approach to delay, slow or completely eliminate growth of cancer within bone.Read moreRead less
V-ATPases Subunit D2 Is Critical For Acdification And Bone Resorption.
Funder
National Health and Medical Research Council
Funding Amount
$531,264.00
Summary
Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, aci ....Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption. Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast function and bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone disordersRead moreRead less
Impaired Bone Remodelling Leads To Failure Of Orthopaedic Prostheses
Funder
National Health and Medical Research Council
Funding Amount
$515,917.00
Summary
The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%, meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is becoming more common for young, active in ....The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%, meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is becoming more common for young, active individuals to receive joint replacement surgery to improve their quality of life. This, combined with increasing life expectancy, and the known higher rate of failure of joint replacements in younger patients, means that the morbidity of a failed replacement, and the mobidity and associated mortality of revision surgery, will become an increasingly important health issue, with a major impact upon health budgets. The overwhelming majority of hip and knee prostheses have metal or ceramic on polyethylene bearing surfaces. It is now apparent that most implants fail due to bone loss around them leading to loosening, and evidence is accumulating that polyethylene wear particles are a major contributing factor to this process. It is therefore vital that we obtain better understanding of the causes of implant failure in order to extend the life of these implants and this project is designed to do so.Read moreRead less
Caltrin As A Calcium Transport Inhibitor During Osteoclastic Bone Resorption
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Excessive bone resorption has been observed in many common bone diseases such as osteoporosis, Paget's disease and arthritis. These are major health problems in Australia and other developed countries. Increased activation or formation of osteoclasts is responsible for the excessive bone resorption. Understanding the mechanisms by which the osteoclasts exert its function and activation is an important step toward developing strategies to combat excessive bone resorption for the treatment and pre ....Excessive bone resorption has been observed in many common bone diseases such as osteoporosis, Paget's disease and arthritis. These are major health problems in Australia and other developed countries. Increased activation or formation of osteoclasts is responsible for the excessive bone resorption. Understanding the mechanisms by which the osteoclasts exert its function and activation is an important step toward developing strategies to combat excessive bone resorption for the treatment and prevention of osteolytic disorders. This project attempts to address the important and fundamental issue of osteoclast function. We have identified caltrin, a known calcium transport inhibitor, that is likely to be biologically important in osteoclast calcium homeostasis. This project intends to investigate the role of caltrin in calcium-induced apoptosis, osteoclast bone resorption and the cellular and molecular mechanisms underlined. It will enhance our knowledge of calcium regulation in osteoclasts and provide information to facilitate the development of new anti-resorptive agents.Read moreRead less
The Role Of V-ATPase Accessory Subunit Ac45 In Osteoclasts
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus of bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular target for the discovery of novel bone antiresorptive ag ....Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus of bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular target for the discovery of novel bone antiresorptive agents useful for the treatment of lytic bone disorders. The proposed research will give considerable insight into the role of the both V-ATPase accessory subunit Ac45 and V-ATPase complex in osteoclasts. Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone disorders.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
The Risks And Benefits Of Contemporary Total Hip Replacement
Funder
National Health and Medical Research Council
Funding Amount
$493,530.00
Summary
The number of hip replacements undertaken in Australia is steadily increasing. The most common complications of hip replacements are dislocation and loosening due to bone loss around the implant, requiring complex and expensive revision surgery. This study will investigate the incidence of dislocation and, using a new diagnostic imaging technique, the incidence and amount of bone loss around a relatively new prosthetic material, the outcomes of which are not known despite its increasing use.