The Role Of Androgens In Osteoblast Development And Bone Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$64,631.00
Summary
Male hormones are essential for the growth and maintenance of bone in men, but exactly how and when they act on the bone forming cells is unclear. We aim to find out what happens when the target for male hormones (receptor) is removed in the bone forming cells at different stages of their development. This project will increase our understanding of how male hormones regulate bone formation and may assist in the design of new therapies for osteoporosis.
Cellular Responses To Thrombin In Skeletal Pathology
Funder
National Health and Medical Research Council
Funding Amount
$120,775.00
Summary
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also causes bone cells to alter their behaviour. Thrombin stimulates proliferation of bone-forming cells and protects them from premature death. Thrombin also stimulates t ....Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also causes bone cells to alter their behaviour. Thrombin stimulates proliferation of bone-forming cells and protects them from premature death. Thrombin also stimulates the breakdown of bone. We will investigate how thrombin's effects on bone cell behaviour influence the course of bone healing. We will also determine how thrombin stimulates bone breakdown and increases survival of bone-forming cells. This study will contribute to the understanding of how bone cells function in health and disease.Read moreRead less
The Role Of Protease-activated Receptor-2 In Regulation Of Bone Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$216,100.00
Summary
Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. We have recently demonstrated the presence of a receptor called PAR-2 on bone-forming cells. We have also shown that activation of PAR-2 inhibits the development of bone-resorbing cells (osteoclasts) in response to hormones. We ....Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as well as in the skeleton's response to disease. We have recently demonstrated the presence of a receptor called PAR-2 on bone-forming cells. We have also shown that activation of PAR-2 inhibits the development of bone-resorbing cells (osteoclasts) in response to hormones. We plan to investigate the mechanism of this effect, as well as to identify how PAR-2 activation modulates other responses of bone cells to hormones. Molecules that activate PAR-2 are present in bone in certain disease situations, but it is not known what activates PAR-2 in bone under normal conditions. We will identify physiological activators of PAR-2 within bone.Read moreRead less
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in which they work to determine whether they may be good targets for new osteoporosis treatments. We will examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop and function, to determine when the genes are expressed and how they function. We will test the ability of the candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less
Osteoblast Control Of Mesenchymal Progenitor Cell Differentiation: The Role Of Glucocorticoids And Wnt Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$443,131.00
Summary
Osteoporosis is an important and growing health issue. Reduced ability to make new bone is an important cause of osteoporosis. In this project we will study how the immature cells which eventually make bone are recruited and controlled. In particular, we will study how genes coding for important growth factors are regulated so that the proper signals are sent to young cells to induce them to become bone-making rather than fat-making cells.
Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone Formation By Genetic Overexpression.
Funder
National Health and Medical Research Council
Funding Amount
$440,750.00
Summary
This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover whe ....This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover when compared to normal mice. We believe this will occur via the effect of prostaglandins on expression of genes that control osteoclast formation. This will be tested by examining the structure of the skeleton, and the expression of certain genes, in transgenic mice at different ages from 2-8 months. These effects may be exacerbated in conditions of increased bone turnover, such as postmenopausal bone loss. This will be tested by examining the bone structure and gene expression in adult mice following removal of their ovaries. Due to the role of COX-2 in adaptation of bone to mechanical loading, we also expect the load-bearing skeleton to be more sensitive to increased weight-bearing activity. We will investigate this hypothesis by applying mechanical loads to the tibiae of mice in a controlled manner and then analysing the bone structure. Knowledge of specific pathways by which bone formation can be stimulated is important for developing novel approaches to induction and augmentation of osteogenesis in skeletal diseases associated with ageing or disability, or for maintenance of new bone around implants. The discovery that COX-2 is a key enzyme in mechanotransduction and osteoclastogenesis in bone, and a pharmacological target for modulating inflammation, has considerable clinical significance. Exploiting this knowledge requires precise knowledge of the role of this enzyme in bone remodelling and adaptation and our experiments will contribute significantly to that knowledgeRead moreRead less
The Mechanisms Of The Anabolic Actions Of Androgens In Bone.
Funder
National Health and Medical Research Council
Funding Amount
$470,960.00
Summary
Androgens (male sex hormones) are one of the few agents that increase bone formation. Androgens act by binding to a specific protein, the androgen receptor (AR). To understand exactly how androgens increase bone formation, we will study mice in which the AR is inactivated only in bone forming cells at specific stages of their development. Understanding the way in which androgens act on bone to increase size and strength will be of great benefit in the design of new treatments for osteoporosis.