The Role Of P62/A170 In Pathological Bone Destruction
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose ....Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62-A172 may play an important part in the switch off-on signals necessary for bone resorbing cells to resorb bone. To this end, we will study the molecular mechanism of P62 in action, and the interaction with its possible partners for the facilitation of abnormal bone resorption. The clinical significance of this project is to: 1) enhance understanding of abnormal bone resorption in Orthopaedic related diseases and conditions. 2) provide a strategy of drug development for the treatment of these disease and conditions.Read moreRead less
Tissue Engineering Approach To Musculoskeletal Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$622,655.00
Summary
Over the next few decades there is an anticipated steady increase in surgical intervention for bone, cartilage and tendon damages due to trauma or osteoporosis as a consequence of an aging population. These damages cause chronic pain, immobility, restricted activities, and, sometimes, death and are a considerable financial burden to the Australian Health System.
The Therapeutic Value Of Targeting Wnt Signalling For The Treatment Of Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$561,535.00
Summary
Osteoarthritis (OA) affects 1.62 million Australians and imposes a significant burden on healthcare. It is characterised by damage to joint cartilage, and increased bone formation with formation of bone spurs. Our studies will determine the importance of the Wnt signalling pathway in mediating OA joint degeneration and identify mechanisms that regulate the activation of this pathway in OA. This will inform the development of novel therapeutic strategies which could halt joint damage in OA.
Long-term In Vivo Imaging Of Bone Marrow Microenvironments In Multiple Myeloma.
Funder
National Health and Medical Research Council
Funding Amount
$688,371.00
Summary
White blood cells are soldiers of the immune system. When the machinery that controls growth and death of these cells is disrupted, these cells can undergo massive expansion. This leads to the development of blood cancers such as multiple myeloma (MM). In MM, malignant cells infiltrate bones preventing production of blood and damaging the bone structure leading to fractures. Using cutting edge microcopy we will watch how MM cells grow and damage bone tissue to develop new therapeutic approaches.
Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better i ....Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better investigate the mechanisms of the bone loss. Drugs to stop the loss of bone have only recently been available to patients and many new treatments are being developed. While most of these drugs are proving useful to treat osteoporosis, their suitability for the treatment of bone loss in diseases such as periodontal disease, rheumatoid arthritis and peri-implant osteolysis is largely unknown. As the way bone is lost in these inflammatory diseases quite different from osteoporosis different treatments are needed. This project aims to better understand bone loss in these diseases and identify new treatments to prevent the debilitating bone loss associated with inflammation in disease.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
Regulation Of Bone Resorption In Periodontal Disease
Funder
National Health and Medical Research Council
Funding Amount
$258,500.00
Summary
Periodontal disease is the most common disease involving bone loss in the world. We know little about the causes and how the disease develops. Some of the bacteria that live in the mouth are associated with the disease but the presence of these bacteria does not mean a person will have it. We do not know why some people suffer from the disease and others do not. Unfortunately when a person has periodontal disease the dentist has few choices in the way in which the patient is treated. There are n ....Periodontal disease is the most common disease involving bone loss in the world. We know little about the causes and how the disease develops. Some of the bacteria that live in the mouth are associated with the disease but the presence of these bacteria does not mean a person will have it. We do not know why some people suffer from the disease and others do not. Unfortunately when a person has periodontal disease the dentist has few choices in the way in which the patient is treated. There are no drugs presently available to treat this disease and surgical removal of the diseased tissue is the only option for treatment. Often after this treatment the disease continues to get worse and more bone is lost sometimes resulting in the loss of teeth. This study aims to understand how the disease causes the bone loss. We believe that some newly identified factors that regulate the cells which destroy bone are responsible. Our recently works show that these factors are present in abnormal levels in the diseased tissues of patients. We also wish to go further and try and find ways of treating the disease. We aim to find new treatments based on controlling the factors that regulate the cells that destroy bone .Read moreRead less
Is Bisphosphonate Use For The Treatment Of Benign Bone Disease Associated With Impaired Dental Healing?
Funder
National Health and Medical Research Council
Funding Amount
$238,160.00
Summary
Osteoporosis (OSP) is a common condition where bones are thin and may break (fracture). Currently, approximately 2 million Australians suffer from OSP. This figure will rise over the next 20 years as people age. Recommended drug treatment of OSP involves medication called bisphosphonates. Recent research, including a warning from the National Adverse Drug Reaction Committee, has suggested a possible association between bisphosphonates and bone breakdown in the jaw (osteonecrosis) - a devastating ....Osteoporosis (OSP) is a common condition where bones are thin and may break (fracture). Currently, approximately 2 million Australians suffer from OSP. This figure will rise over the next 20 years as people age. Recommended drug treatment of OSP involves medication called bisphosphonates. Recent research, including a warning from the National Adverse Drug Reaction Committee, has suggested a possible association between bisphosphonates and bone breakdown in the jaw (osteonecrosis) - a devastating condition for which no effective treatment exists. This study seeks to determine if bisphosphonate use for the treatment of OSP or other non-cancerous (benign) bone disease (eg Paget's disease) slows dental healing and increases the risk of jaw osteonecrosis. This has major implications and significant potential benefits for the large numbers of people with OSP taking bisphosphonates. Currently, the chance of dental complications during bisphosphonate therapy and what factors predispose to such complications remains unclear. Given the large numbers of people at risk, these are important issues that require urgent careful investigation. We want to determine if long-term (more than 2 years' duration) bisphosphonate treatment of OSP or other benign bone disease slows dental healing and leads to jaw osteonecrosis. We will use a case-control study design given the expected low likelihood of slowed dental healing. This design involves identifying patients with slowed dental healing (cases), and patients with normal dental healing (controls). Cases and controls will then be compared for bisphosphonate use to see if it is more likely that cases have been taking bisphosphonates. Our results will help guide treatment recommendations for these drugs both nationally and internationally.Read moreRead less
The Role Of CXCL12 (SDF-1)/CXCR4 In Pathological Angiogenesis And Osteolytic Bone Disease In Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$665,896.00
Summary
Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine mol ....Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine molecule called CXCL12 which acts as a calling card for plasma cells to leave the lymph node and migrate to the BM. Once within the BM, the cells rapidly grow in response to BM-derived growth factors. This rapid growth causes a depletion in oxygen availability within the tumour and it becomes hypoxic. In response to this hypoxia, the tumour expresses a gene called hypoxia-inducible factor-1 (HIF-1) which regulates the expression of many proteins, including the chemokine CXCL12. Our studies show that the abnormal expression of CXCL12 by the plasma cells acts to promote blood vessel formation within the tumour, which in turn leads to greater tumour growth. In addition, our studies suggest that abnormal CXCL12 expression also promotes the recruitment and activation of large numbers of osteoclast (OC) precursors form the peripheral blood. OC are cells which normally remove unwanted or damaged bone. This proposal will study the interplay between HIF and CXCL12 in the establishment and development of MM and the associated bone destruction.Read moreRead less
Artificial joint implants are widely used to replace diseased or damaged joints. Despite the impressive success of joint replacement many artificial joints do not last indefinitely. In many patients joints last for 25 years or more but in about 15% the artificial joints will fail prematurely. Artificial joints need to be replaced because of loosening resulting from the loss of bone from around the artificial joint. The bone loss is caused by large numbers of small particles generated by excessiv ....Artificial joint implants are widely used to replace diseased or damaged joints. Despite the impressive success of joint replacement many artificial joints do not last indefinitely. In many patients joints last for 25 years or more but in about 15% the artificial joints will fail prematurely. Artificial joints need to be replaced because of loosening resulting from the loss of bone from around the artificial joint. The bone loss is caused by large numbers of small particles generated by excessive wear of the artificial joint. We now know that specialised cells in the body react to the wear particles and try to destroy them. During this process they produce molecules which lead to bone destruction. This project seeks to investigate the way particles cause bone loss and to develop drug treatments that will either prevent the loss of bone or promote new bone to replace that which has been lost. The increasing use of joint replacement and an aging population means that the number of patients with artificial joint failure will increase. This will mean that an increasing amount of medical recourses will be needed to replace failed and painful artificial joints. It is planned that the findings obtained from this project will eventually result in drug treatments which can reduce the need for the replacement of artificial joints.Read moreRead less