SPARC Induced Tendon Differentiation And Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$154,718.00
Summary
Tendinopathy has a significant patient morbidity, which is a clear burden to the Australian economy. A better fundamental grasp of tendon tissue biology is urgently required. This study will enable us to establish the role of matricellular protein SPARC in tendon function, thus enhance the understanding of tendon biology and enable translation of the bench work to potential clinical applications.
Artificial joint implants are widely used to replace diseased or damaged joints. Despite the impressive success of joint replacement many artificial joints do not last indefinitely. In many patients joints last for 25 years or more but in about 15% the artificial joints will fail prematurely. Artificial joints need to be replaced because of loosening resulting from the loss of bone from around the artificial joint. The bone loss is caused by large numbers of small particles generated by excessiv ....Artificial joint implants are widely used to replace diseased or damaged joints. Despite the impressive success of joint replacement many artificial joints do not last indefinitely. In many patients joints last for 25 years or more but in about 15% the artificial joints will fail prematurely. Artificial joints need to be replaced because of loosening resulting from the loss of bone from around the artificial joint. The bone loss is caused by large numbers of small particles generated by excessive wear of the artificial joint. We now know that specialised cells in the body react to the wear particles and try to destroy them. During this process they produce molecules which lead to bone destruction. This project seeks to investigate the way particles cause bone loss and to develop drug treatments that will either prevent the loss of bone or promote new bone to replace that which has been lost. The increasing use of joint replacement and an aging population means that the number of patients with artificial joint failure will increase. This will mean that an increasing amount of medical recourses will be needed to replace failed and painful artificial joints. It is planned that the findings obtained from this project will eventually result in drug treatments which can reduce the need for the replacement of artificial joints.Read moreRead less
Tendon injury is one of the most common health problems worldwide and affects almost everyone at some point in particular the aging populaiton. However, the current treatments are not well defined. We identifed an extracellular molecules SPARC that potentially plays an important role in tendon function. The aim of this study is to examine the role of SPARC in tendon development, homestasis and degenerative using transgenic mice and gene therapy. We predict that SPARC will have therapeutic value ....Tendon injury is one of the most common health problems worldwide and affects almost everyone at some point in particular the aging populaiton. However, the current treatments are not well defined. We identifed an extracellular molecules SPARC that potentially plays an important role in tendon function. The aim of this study is to examine the role of SPARC in tendon development, homestasis and degenerative using transgenic mice and gene therapy. We predict that SPARC will have therapeutic value for the treatment of tendinopathy.Read moreRead less
The Role Of Muscle And The Application Of Muscle-cell Therapies In Bone Repair
Funder
National Health and Medical Research Council
Funding Amount
$438,936.00
Summary
Muscle is often close to bone and we have found that muscle cells can directly contribute to bone repair. We are examining importance of muscle cells in orthopaedic repair and whether new methods for mobilizing muscle cells can improve healing.
Novel Roles For IL-33 In The Maintenance Of Bone Mass And As A Locally Derived Anabolic Factor For Bone
Funder
National Health and Medical Research Council
Funding Amount
$592,574.00
Summary
Over 10% of the population have thin, brittle bones that fracture easily, and is often seen in elderly people. When diagnosed, a fracture has usually already occurred and the bone is already thin. Drugs are available to stop further bone weakening, but building new bone would be best. We have found a protein in bone that reduces bone loss and stimulates bone formation processes. This project seeks to determine how this protein works and how to exploit it to design new bone building therapies.
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
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
Structural And Functional Analyses Of Rat Receptor Activator Of NF-kb Ligand
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fra ....Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. This proposal addresses the important and fundamental issue of RANKL regarding the role of molecular structure on its biological function. We have established that the TNF-like core domain is the functional domain, important for osteoclastogenesis, osteoclast polarisation and protecting against Fas-triggered apoptosis. This proposal will further characterise the mutant forms of the TNF-like core domain of RANKL using site directed mutagenesis and protein truncation analysis, and assess their respective binding activities to OPG and RANK, and their biological activities both in vitro and in vivo. It will lead us into better understanding of the structure-function relationship of RANKL. Ideally, we would like to develop a relative agent for the suppression of osteolysis in orthopaedic related diseases including osteoporosis. Such an optimized molecule could become a potent therapeutic agent that selectively inhibits osteoclast formation and bone resorption.Read moreRead less
Role Of Bone-associated Macrophages In Bone Remodelling And Bone Disease
Funder
National Health and Medical Research Council
Funding Amount
$564,963.00
Summary
Musculoskeletal diseases, including osteoporosis and osteoarthritis, are a national and international health and research priorities. Over 3 million Australians suffer from arthritis and musculoskeletal conditions and their social and economic impact is expected to dramatically increase in the next 20 years as a result of the aging population. Early diagnosis, prevention and treatment of many musculoskeletal diseases are currently inadequate. Consequently, there is a high demand for effective tr ....Musculoskeletal diseases, including osteoporosis and osteoarthritis, are a national and international health and research priorities. Over 3 million Australians suffer from arthritis and musculoskeletal conditions and their social and economic impact is expected to dramatically increase in the next 20 years as a result of the aging population. Early diagnosis, prevention and treatment of many musculoskeletal diseases are currently inadequate. Consequently, there is a high demand for effective treatment options. This project grant application proposes a novel line of scientific investigation that will provide greater understanding of the contribution of macrophages (a cell type that has important roles in normal tissue maintenance and defense against infection) in bone remodelling and disease. Bone is continuously remodelled and replaced to maintain skeletal strength and mineral metabolism. We have shown that a population of macrophages is intimately associated with bone and propose that these cells play an important part in regulating bone remodelling. Macrophages have been implicated in many diseases that have damaging consequences on bone, including osteoporosis and several forms of arthritis, linking aberrant macrophage function to disease-associated bone damage. This project aims to characterize this population of bone-associated macrophages and determine their ability to influence the function of other cells integrally involved in bone remodelling. We will also undertake studies in animal models to determine whether these cells are required for bone remodelling and-or damage. Detailed description of the novel role of macrophages in bone biology will facilitate the development of superior therapeutics, preventatives and cures for bone diseases.Read moreRead less