Breast Cancer has a particular preference to form cancer metastases in bone where its presence is associated with bone destruction that frequently results in significant pain and disability. Bone seems to provide a fertile soil for breast cancer cells that have moved into the blood vessels from the original cancer site in the breast. Once tumour cells have invade bone marrow spaces from the blood vessels they are able to grow and induce the normal cells of the bone marrow to destroy the surround ....Breast Cancer has a particular preference to form cancer metastases in bone where its presence is associated with bone destruction that frequently results in significant pain and disability. Bone seems to provide a fertile soil for breast cancer cells that have moved into the blood vessels from the original cancer site in the breast. Once tumour cells have invade bone marrow spaces from the blood vessels they are able to grow and induce the normal cells of the bone marrow to destroy the surrounding hard bone. This allows the tumour to grow faster. Together these processed create a vicious cycle that contributes to the serious consequences of bone metastases. In this project we will be studying mice with breast cancer to understand what makes the bone marrow such a fertile and receptive site for breast cancer metastasis. In particular, we are looking at how the normal processes of bone renewal and repair contribute to the establishment of cancer in bone. We will use the body's own bone protecting protein, called osteoprotegerin, to test how blocking bone destruction will affect the ability of cancer cells to invade and grow in bone. This study has the potential to change the way bone metastases are treated. Treatment of breast cancer could be significantly improved if the fertile soil of bone could be modified to either block the targeting of breast cancer to bone, or to inhibit its growth there.Read moreRead less
Novel Strategies For The Treatment Of Bone Disease By Nutrient Activators Of Calcium-sensing Receptors
Funder
National Health and Medical Research Council
Funding Amount
$467,432.00
Summary
Osteoporosis is a major health problem in the Australian community and will worsen with an ageing population. This work aims to develop new strategies for the treatment of osteoporosis and associated fractures based on the nutritional and/or pharmacological activation of calcium-sensing receptors.
Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and can therefore be targeted with similar therapies. However, litt ....Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and can therefore be targeted with similar therapies. However, little is known of the response properties, structure and organization of receptors and neurones responding to, and relaying information about painful stimuli, from bone to the brain. The objectives of this project are to reveal the fundamental neural mechanisms that account for the perception of bone pain. The project will test a series of specific hypotheses in order to explain why bone pain is often poorly controlled by standard pharmacological or surgical approaches. It is expected that this study will reveal the neural mechanisms responsible for relaying sensory information, in particular, that regarding painful stimuli, from bone to the brain. It will lead to a better understanding of the mechanisms of bone pain and form the template for future studies of its treatment.Read moreRead less
Trabecular Architecture During Growth - Does It Determine Metaphyseal Peak Bone Strength In Adulthood?
Funder
National Health and Medical Research Council
Funding Amount
$165,339.00
Summary
Skeletal fragility is common is elderly people but has its origin in childhood. Strong bone established during growth will provide more protection against occurrence of fragility fracture in old age. Identifying individuals during childhood who are at high risk of skeletal fragility, and early intervention is a strategic approach managing the burden of skeletal fragility on the ageing population.
The Molecular Mechanisms Controlling Maintenance Of Osteogenic Precursor Cells And Skeletal Tissue Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$234,750.00
Summary
Within human bone marrow there exists a rare population of bone marrow stromal stem cells (BMSSCs) able to develop into the different cell types that form haematopoietic supportive stroma and surrounding skeletal tissue. There has been alot of interest of late in the potential of BMSSCs as a cellular based therapy to treat and manage bone fractures or bone loss caused by disease. Increasing evidence suggests that decreased bone mass due to osteoporosis dos not purely result in an increase of bon ....Within human bone marrow there exists a rare population of bone marrow stromal stem cells (BMSSCs) able to develop into the different cell types that form haematopoietic supportive stroma and surrounding skeletal tissue. There has been alot of interest of late in the potential of BMSSCs as a cellular based therapy to treat and manage bone fractures or bone loss caused by disease. Increasing evidence suggests that decreased bone mass due to osteoporosis dos not purely result in an increase of bone resorption by osteoclasts, but may also occur through a decline in the number of bone forming cells called osteoblasts or their progenitors. Fracture non-union, prosthetic loosening and the replacement of large defects in bone are common and difficult problems. The use of autologous bone cells generated from isolated BMSSCs in combination with bio-compatible implant materials would provide a novel solution for the treatment of these problems, avoiding the use of autografts and allografts of bone with all their associated difficulties. However, large numbers of ex vivo expanded BMSSCs are currently required to heal even small bone defects in animal models. This is compounded by the decline in proliferation rates and bone forming capacity of BMSSCs during prolonged expansion in culture. An improved understanding of the genes that regulate the proliferation and differentiation of BMSSCs in vitro is therefore an essential prerequisite for the effective management of bone fracture and bone loss. We propose to genetically manipulate the expression of genes in BMSSCs, that are known to regulate cellular growth and development inorder to maintain the growth of stem cell populations in vitro and to extend their capacity to form bone when transplanted in vivo.Read moreRead less
The Role Of TWIST Family Basic Helix-Loop-Helix Transcription Factors In Bone Cell Commitment, Function And Repair
Funder
National Health and Medical Research Council
Funding Amount
$485,928.00
Summary
In developed countries, projected estimates predict an alarming trend of a two to three fold increase in the number of fractures that require surgical intervention and rehabilitation therapy in the coming decades as a consequence of an aging population. Fracture healing is a complex physiological process that involves the coordinated participation of different bone marrow cells, immune cells and skeletal progenitor cells. Multiple factors regulate interactions between these cell types that influ ....In developed countries, projected estimates predict an alarming trend of a two to three fold increase in the number of fractures that require surgical intervention and rehabilitation therapy in the coming decades as a consequence of an aging population. Fracture healing is a complex physiological process that involves the coordinated participation of different bone marrow cells, immune cells and skeletal progenitor cells. Multiple factors regulate interactions between these cell types that influence the capacity of bone cell progenitors to develop into functional bone forming cells known as osteoblasts. An understanding of the fracture healing is critical for the future advancement of fracture treatment, and for identifying the mechanisms of skeletal growth and repair as well as the causes of aging and disease. This proposal seeks to identify critical regulatory molecules that act to mediate bone cell progenitor recruitment and development during bone fracture repair.Read moreRead less
Relationships Between Human Osteoblasts And Haemopoietic Cells In Bone Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$436,450.00
Summary
Bone diseases, such as osteoporosis and osteoarthritis, currently afflict more than 4 million Australians. These diseases are characterised by abnormal bone remodelling, which can result in a net loss of bone (for example, in osteoporosis) or abnormal bone structure (for example, in osteoarthritis). We are seeking to better understand the factors that regulate bone remodelling, and particularly the cells involved in this process. Physiological bone remodelling results from the intimate collabora ....Bone diseases, such as osteoporosis and osteoarthritis, currently afflict more than 4 million Australians. These diseases are characterised by abnormal bone remodelling, which can result in a net loss of bone (for example, in osteoporosis) or abnormal bone structure (for example, in osteoarthritis). We are seeking to better understand the factors that regulate bone remodelling, and particularly the cells involved in this process. Physiological bone remodelling results from the intimate collaboration between osteoblasts and osteoclasts. Osteoblasts stimulate the formation of osteoclasts and also produce new bone at resporption sites. However, the way that the same type of cell can perform both these tasks, is not clear. Our studies are designed to increase our understanding of the development of human osteoblasts and of the factors that cause them to be sequentially pro-osteoclastic and then pro-osteogenic. We believe that an important factor in this process is vitamin D and we will test the hypothesis that this molecule is produced in bone and acts locally to regulate bone turnover.Read 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