The Role Of Androgens In Osteoblast Development And Bone Metabolism.
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Maintenance of the skeleton involves the processes of bone formation by cells known as osteoblasts and bone breakdown by cells known as osteoclasts. When these processes become unbalanced, bone loss results, which is the basis of osteoporosis. The reduced bone mass found in osteoporosis leads to an increased susceptibility to bone fracture. 1 in 2 women and 1 in 3 men over the age of 60 will suffer a fracture due to osteoporosis. The increasing incidence of osteoporotic fractures has lead to ren ....Maintenance of the skeleton involves the processes of bone formation by cells known as osteoblasts and bone breakdown by cells known as osteoclasts. When these processes become unbalanced, bone loss results, which is the basis of osteoporosis. The reduced bone mass found in osteoporosis leads to an increased susceptibility to bone fracture. 1 in 2 women and 1 in 3 men over the age of 60 will suffer a fracture due to osteoporosis. The increasing incidence of osteoporotic fractures has lead to renewed efforts to understand the actions of hormones on bone. Androgens, the male sex hormones, have beneficial effects on skeletal growth and bone maintenance in both males and females by stimulating osteoblasts. It is believed that androgens act by binding to a specific protein known as the androgen receptor (AR), which is only found in androgen-responsive cells. Although it is well documented in human and animal models that androgens stimulate osteoblasts to increase the formation of bone, the way in which they act on osteoblasts remains poorly understood. The aim of this project is to investigate the effects of androgens at different stages of the developing osteoblast. This will be achieved by making transgenic mice in which the androgen receptor has been inactivated only in osteoblasts at specific stages of their development. We hypothesise that the inactivation of the androgen receptor will have dramatic effects on the development and function of osteoblasts. This project will help clarify the role androgens play in bone formation and will give fundamental insights into the basic biology of bone in both normal and disease processes. As androgens are one of the few agents that act to increase bone formation, understanding the way in which they act is important for the treatment of osteoporosis in males and females. We believe that this research is of great importance as osteoporosis becomes more prevalent in our aging population.Read moreRead less
Molecular Characterization Of V-ATPase V0 Domain Subunits E1 And E2 In Osteoclast
Funder
National Health and Medical Research Council
Funding Amount
$558,909.00
Summary
Osteoporotic fractures in the elderly are often linked to increased mortality rates. Excess bone resorption is a major contributor to the onset of the disease. The proposed project focuses on the investigation of the molecular mechanisms of acid secretion that is required for the bone degradation in body. The project will examine the role of the proton pump in bone resorption and seek potential targets for the treatment of osteoporosis.
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
Extracellular Signal-Regulated Kinases 1 And 2 Activity In Osteoarthiritis
Funder
National Health and Medical Research Council
Funding Amount
$387,071.00
Summary
Osteoarthritis (OA) is the most common form of joint disorders and a major cause of disability in the elderly, affecting approximately 60% of men and 75% of woman above the age of 65. This project will specifically focus on the regulatory role of cell signaling pathways in OA development and progression. The outcome of this project is the potential to develop early intervention treatments of osteoarthritis.
Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to introduce novel successful therapies. We believe that a improved understanding of the origins of the cells involved with bone healing may lead to new surgical, drug and cell-based therapies for the treatment of recalcitrant bone repair. Stem cells originating from the bone marr ....Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to introduce novel successful therapies. We believe that a improved understanding of the origins of the cells involved with bone healing may lead to new surgical, drug and cell-based therapies for the treatment of recalcitrant bone repair. Stem cells originating from the bone marrow and periosteum are known to differentiate into mature bone cells and produce bone. However, these tissues are damaged or have poor access to the site of bone injury in many severe open fractures. In these cases, bone repair often initiates in a region adjacent to an opposing muscle. This has led us to speculate that cells from the muscle may directly contribute to bone repair. Published studies, which have be confirmed by our group, have demonstrated the strong potential for muscle-derived progenitor cells (satellite cells) to become bone-like in response to stimuli such as bone morphogenic proteins. To put bone-forming potential of muscle cells in perspective, we plan to expand on these studies and compare mouse satellite cells with mouse bone marrow stem cells. In addition, we plan to use a transgenic mouse whose muscle cells become permanently genetically transformed to stain blue. This mouse will allow us to assess the fate of muscle cells and their contribution to bone formation in ectopic bone formation and fracture repair models. This study will explore on the most basic level the cellular contribution of muscle to bone repair. The results of this research project will significantly influence our therapeutic directions for improving fracture repair in the future.Read moreRead less
Rotator cuff (RC) tendon disease is a huge burden on the healthcare system in Australia and a major cause of morbidity in our aging population. Disorders of the RC are the most common cause of shoulder pain, which accounts for 1.2% of all visits to general practitioners. The prevalence of RC pathology increases with age to reach 30-50% by the seventh decade of life and a staggering 70-80% by the ninth. While most cases are treated conservatively, there are over 12,000 RC repair surgeries perform ....Rotator cuff (RC) tendon disease is a huge burden on the healthcare system in Australia and a major cause of morbidity in our aging population. Disorders of the RC are the most common cause of shoulder pain, which accounts for 1.2% of all visits to general practitioners. The prevalence of RC pathology increases with age to reach 30-50% by the seventh decade of life and a staggering 70-80% by the ninth. While most cases are treated conservatively, there are over 12,000 RC repair surgeries performed annually in Australia, with patients being committed to a prolonged convalescence. There are no drug therapies to specifically treat RC or other tendon injuries and many surgical repairs fail within 12 months. The limited treatment options for RC and other tendon disorders stems from a lack of knowledge of the molecular changes that precede and lead to rupture. It is recognised that the content of sulphated sugars or glycosaminoglycans (GAGs) on proteoglycans in tendon is the strongest predictor of the tisues strength. Accumulation of GAG is a well-recognised feature of torn tendons in man. The changes in proteoglycan synthesis and breakdown that precede and lead to tendon rupture have not been defined. We have developed a new model of shoulder tendon injury in sheep that induces regional degeneration mimicking that seen in human RC disorders. We have found changes in expression of specific proteoglycans and their degradative enzymes in early tendon disease. The current project will use this model in combination with a novel culture system and recently developed genetically modified mice to determine for the first time the changes that occur over time in proteoglycan metabolism that are responsible for tendon degeneration that leads to rupture. Successful completion of these studies will identify biomarkers to monitor disease progression and a platform for the development of new therapeutic strategies to treat this debilitating disorder.Read moreRead less
Degeneration and tearing of tendons such as the rotator cuff is a major health issue in working and ageing Australians. Tendon ruptures are preceded by degenerartive change which contributes to the poor success with surgical repair. There are very limited medical treatments available. We have developed an animal model mimicing human tendon dgeneration and will determine the utility and mechanisms of action of using a novel new therapy, stem cells in modulating degenerarion and aiding repair.
Cell Biology Of Stress Fractures: Activation Of Remodelling At Sites Of Non-union
Funder
National Health and Medical Research Council
Funding Amount
$493,817.00
Summary
Stress fractures are debilitating injuries. We characterised a model of stress fractures in rat ulnae, learning that they heal by activated remodelling, that key genes are expressed in a temporal pattern, and that part of the fracture remains un-healed, similar to many clinical cases. Now, we will examine cell localisation of important genes necessary for remodelling, and test the efficacy of different growth factors to activate a healing response in the non-healed section of the fracture.