Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. ....Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. OCs are formed from white blood cells that are present in the bone marrow and the blood. The recent discovery of a family of new factors that control the formation of OCs has enabled the generation of human OCs in the laboratory so now we can investigate the genes that control the process of conversion of white blood cells to OCs. An important advance in this project involves the use of cord blood that contains stem cells. These very na ve cells will enable us to study the very earliest genes that control differentiation of precursors to OC. We have found a number of genes that are regulated by these new bone-forming factors. In white blood cells the activation of particular genes can regulate OC formation. One example is vitamin D-upregulated gene, VDUP. This gene is of particular interest as it causes inhibition of the mechanism that leads to OC formation in the bone. Obviously, the ability to control a 'switch' that regulates OC formation may enable us to control the progress of bone loss in diseases such as osteoporosis. In this project, we intend to investigate how and why the genes that lead to OC formation are regulated and what influence the various bone cell factors have on the formation of bone-resorbing OCs. These studies will lead to the development of treatments for osteoporosis and other bone diseases.Read moreRead less
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
We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons wh ....We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons who are overweight tend to have higher circulating blood levels of leptin and also tend to have denser bones, which suggests that there might be a relationship between blood leptin and bone density or strength. Furthermore, leptin is produced in the bone marrow which is where osteoclasts are produced. Osteoclasts are formed from white blood cells which are present in the bone marrow and the blood. Very recent discoveries have identified a family of new factors which play a key role in the formation of osteoclasts. One of these factors has been called osteoprotegerin and is an inhibitor of osteoclast formation. Mutant mice lacking osteoprotegerin have greatly increased numbers of osteoclasts and severe osteoporosis whereas mutants with too much osteoprotegerin have bones which are much denser than normal. The availability of these factors now allows the generation of human osteoclasts in the laboratory which enables the further study of how the process is regulated. We have found that leptin increases the amount of osteoprotegerin produced by white blood cells and we believe that this is the major way that leptin inhibits osteoclast generation. In this project, we intend to further investigate how and why leptin is able to influence the generation and function of osteoclasts as leptin may be a suitable treatment for osteoporosis and other bone diseases.Read moreRead less
Twist-1 Mediated Regulation Of Multipotential Mesenchymal Stem Cell Self-Renewal And Cell Fate Determination
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
In Australia, there is an increasing incidence of fractures and skeletal related problems that require surgical intervention and rehabilitation therapy. These are complex processes that involve the coordination of different bone and immune cells. We will investigate important regulatory molecules that mediate bone-cartilage stem cell recruitment and development during normal skeletal growth and remodelling. This study will help advance therapies for fracture repair and joint deterioration.
The Role Of Eph-ephrin Interactions In Mediating Mesenchymal Stem Cell Commitment, Migration And Bone Fracture Repair
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
In Australia, there is an increasing incidence of fractures that require surgical intervention and rehabilitation therapy. Fracture healing is a complex process that involves the coordination of different bone and immune cells. Our proposal will identify which cell-cell contact molecules mediate bone cell recruitment and development during normal skeletal growth and bone fracture repair. This study will help advance therapies for fracture repair and diseases of bone loss.
Inhibition Of Alloreactivity By Modulation Of Antigen Presenting Cells
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
Bone marrow transplantation (BMT) is the most effect treatment for a number of conditions, especially leukemia. Graft versus host disease (GVHD) is a complication of BMT and results in the death of up to 50% of transplant recipients. GVHD occurs when the newly transplanted immune system recognizes the recipient as foreign and mounts and immune reponse against the patients tissues. These studies will focus on identifying and understanding the function of the immune cells which drive GVHD.
Hematopoietic Effects Of Activating The Hedgehog Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$410,551.00
Summary
The hedgehog proteins are important for normal human development. They are expressed on cells of the brain and developing limbs and provide important signals to neighbouring cells so that development of the brain and limbs can occur normally. Mutations in genes within the hedgehog signalling pathway lead to congenital abnormalities such as failure of the brain to fold properly and shortened limbs or extra digits. Hedgehog proteins also stimulate the growth of adult stem cells that are responsibl ....The hedgehog proteins are important for normal human development. They are expressed on cells of the brain and developing limbs and provide important signals to neighbouring cells so that development of the brain and limbs can occur normally. Mutations in genes within the hedgehog signalling pathway lead to congenital abnormalities such as failure of the brain to fold properly and shortened limbs or extra digits. Hedgehog proteins also stimulate the growth of adult stem cells that are responsible for the maintenance of many adult tissues such as the skin, bone and hair. Excessive hedgehog signalling however can lead to cancers, particularly of the brain and skin. The ability of hedgehog proteins to stimulate the growth of stem cells raises their use for expansion of stem cells. This would be particularly useful for umbilical cord blood stem cells, which could be used to treat patients with leukemia if there were sufficient numbers. This project will examine the potential use of hedgehog proteins for stimulating blood stem cells.Read moreRead less