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
Furin: Carving-up Vital Substrates For Bone Remodelling And Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$815,972.00
Summary
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. It is caused by an imbalance between the cells that are constantly reabsorbing and reforming bone. The proposed project will address furin as a novel regulator of bone remodelling.
Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosi ....Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosis.Read moreRead less
Molecular Mechanisms And Therapeutic Effects Of Novel Parthenolide Analogs On Osteolysis
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Rheumatoid arthritis and osteoporosis are common bone diseases with features of bone loss. Drugs that inhibit bone loss are needed for the prevention and treatment of bone diseases. The proposed research explores the potential use of novel herbal inhibitors for the suppression of bone resorbing cells, and their potential as treatments for bone loss.
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
Molecular Determinants Of Bone Remodelling In The Bone Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$317,640.00
Summary
There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, t ....There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and histomorphometric studies will determine whether the understanding derived from tissue culture and animal experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The elucidation of the molecular signalling in the human bone microenvironment is essential for the effective diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data shows that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further investigate mRNA gene expression of a number of cytokines involved in bone cell signalling and their association with the level of microdamage in the bone. Using a animal model of controlled bone microdamage induction we will seek to determine the bone remodelling causal relationship between microdamage and cytokine signalling. Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are not well understood. These studies will provide new insight into the processes that determine trabecular structures. This project will investigate these mechanisms and increase our understanding of bone cell function, essential for diagnosis and design of rational treatment for bone diseases.Read moreRead less
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 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
Intrinsic Bone Qualities In Fragility Fracture Patients: Mass, Microarchitecture, Mineralization And Damage Accumulation
Funder
National Health and Medical Research Council
Funding Amount
$447,027.00
Summary
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detec ....Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of bone is of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength and fracture toughness (work to fracture) reduce considerably with age. This proposed study would seek to elucidate the role of bone tissue-level properties in determining bone quality for human subjects: patients with fragility hip fractures on no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies, and normal age- and sex-matched individuals. Our laboratory has extensive experience in the analysis of the structure of human bone tissue. Recently, we have developed novel and unique techniques to assess bone quality, using micro-CT, backscatter SEM imaging, confocal microscopy and immunohistochemistry. This multifaceted study will identify at the bone tissue-level the structural mechanisms (micro-architecture, mineralisation, and microscopic cracking) that are indicative of the efficacy of fragility fracture drugs. Better understanding of the mechanisms by which bones are less likely to fracture will enable better targeting of osteoporosis drug therapy to individuals at risk of fragility fracture.Read moreRead less
Interrelationships Between The Disc And Bone Of Lumbar Spinal Segments
Funder
National Health and Medical Research Council
Funding Amount
$423,625.00
Summary
The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal degeneration includes disc degeneration, facet joint osteoarthritis, ....The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal degeneration includes disc degeneration, facet joint osteoarthritis, compromised vertebral body bone quality, muscle and ligament alterations. It is assumed that these changes result in increased or abnormal spine motion and modified load distribution across the spinal joint. It has been found that with age, there is increased disorganisation of the intervertebral disc and decreased quality of vertebral cancellous bone. However, bones with the same density within the range of normal subjects, can show selective loss of bone structure and reduced load-bearing capacities of these vertebrae. An important concept here is that even for a given bone mass, fracture risk increases with age, supporting the view that there is a component of bone fragility that is independent of mass. Increased bone fragility may be associated with compromised cancellous bone structure. While the relationship between disc degeneration and changes in vertebral bone is commonly invoked, the mechanisms of this relationship have largely been overlooked, with age changes given more attention. However, it may be that intervertebral disc disorganisation modulates age-related bone changes within the spine. Disc degeneration may influence trabecular bone responses before changes with age put the patient at risk of vertebral crush fracture. We propose that the mature disc cannot effectively regenerate after damage, and thus responses to disc damage will be more readily observed in vertebral bone architecture than in the disc.Read moreRead less