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.
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
The Role Of CHKB In Osteoclastic Bone Resorption And Bone Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$565,695.00
Summary
Osteoporosis is a devastating disorder. Osteoporotic fractures in the elderly have been correlated with increased mortality rates. Osteoporosis alone costs $13.8 billion p.a. in USA and tens of millions of dollars in Australia. Cost to society of our ageing population for people become disabled by hip fractures alone could triple by the year 2040. Our research examines the role of CHKB in bone loss which may underscore its potential as a new molecular target for anti-resorptive drug development.
Vertebral Body Strength: Contribution Of Bone Mass, Bone Structure And Material Properties
Funder
National Health and Medical Research Council
Funding Amount
$434,498.00
Summary
This study will determine the contributions to vertebral body strength made by its structural and material properties. Using state-of-the-art computed-tomography scanners, digitised representations of vertebral bodies in three-dimensions will be produced, which enable measurement of bone structure. After strength testing of the vertebral bodies, the structural and material properties, which combine to predict vertebral body strength, will be identified in an aged population.