Osteal Macrophages As Therapeutic Targets For Fracture Repair
Funder
National Health and Medical Research Council
Funding Amount
$618,015.00
Summary
Fragility fracture associated with osteoporosis is a substantial health problem costing $1.62 billion to treat in 2012 in Australia. There is no approved therapy to improve and accelerate fracture healing to help reduce this increasing health burden. This research will advance understanding of fracture repair in healthy and osteoporotic bone and progress development of a fracture therapy to improve bone repair by promoting specialised immune cells.
Delayed bone healing can be a considerable problem in both children and adults. Up to 10% of fractures fail to heal properly. An advanced understanding of the cellular responses in bone repair and their manipulation could improve the lives of many patients with orthopaedic problems. These studies will advance out knowledge of interventions to promote bone healing which could be translated rapidly into clinical care.
Why Macrophages Promote Heterotopic Ossifications Following Spinal Cord Injuries
Funder
National Health and Medical Research Council
Funding Amount
$586,950.00
Summary
A frequent complications of brain and spine injuries is the formation of bones outside of the skeleton called "heterotopic ossifications", particularly around joints such as the knee, hip, elbow or shoulder. They grow over a few months to become so large (up to 2 kg) that they block muscles and joints, increasing pain, morbidity and dependance. This project is to understand why heterotopic ossifications form in patients with spine injuries aiming to discover effecttive treatments.
Influence Of Osteocytes On Anabolic Bone Therapies
Funder
National Health and Medical Research Council
Funding Amount
$586,965.00
Summary
This project seeks to define the influence of changes in gene expression in cells called osteocytes, that exist within the substance of bone. These cells form a communication network within the bones of the skeleton, and appear to influence bone formation; changes in gene expression by these cells could influence the efficacy of current and emerging osteoporosis therapies.
Randomised Trial Of Ibuprofen For The Prevention Of Ectopic Bone-related Pain And Disability After Hip Replacement
Funder
National Health and Medical Research Council
Funding Amount
$364,217.00
Summary
Joint replacement is a well-established treatment for severe osteoarthritis of the hip. While most patients benefit substantially from the procedure, many still experience some pain and disability after surgery. New evidence suggests that one important cause of this pain and disability may be abnormal bone deposits that form in the muscles around the hip (ectopic bone formation) during the first few months after surgery. Ectopic bone formation is seen in about 40% of all patients with hip replac ....Joint replacement is a well-established treatment for severe osteoarthritis of the hip. While most patients benefit substantially from the procedure, many still experience some pain and disability after surgery. New evidence suggests that one important cause of this pain and disability may be abnormal bone deposits that form in the muscles around the hip (ectopic bone formation) during the first few months after surgery. Ectopic bone formation is seen in about 40% of all patients with hip replacements. If the formation is extensive, all movement of the hip is lost and revision surgery is necessary. However, even when the formation is less severe, movement at the hip can be restricted resulting in pain and disability. There is growing evidence that treatment with a non-steroidal anti-inflammatory drug at the time of surgery may halve the risk of ectopic bone formation. While this would be expected to decrease the risk and severity of post-operative pain and disability, there is little evidence available about the long-term effects of these drugs after hip replacement. For this reason, together with concerns about possible side-effect of these drugs, orthopaedic surgeons have generally been reluctant to prescribe these drugs routinely for the prevention of ectopic bone formation. Ibuprofen appears to be the non-steroidal anti-inflammatory drug with the lowest risk of side effects. If it was shown to be effective in reducing the incidence of pain and disability associated with ectopic bone formation after hip replacement, it may well be considered worthwhile by doctors and patients alike. If such benefits were realised, this preventive strategy is likely to be a highly cost-effective way to improve long-term outcome among the rapidly growing numbers of patients that receive hip replacements. This study will provide reliable evidence about the short and long-term effects of ibuprofen among 1,000 patients receiving hip replacements in Australia.Read moreRead less
Osteal Macrophages: Novel Regulators Of Osteoblast Function And The Endosteal Stem Cell Niche
Funder
National Health and Medical Research Council
Funding Amount
$406,125.00
Summary
Bone diseases are a major health problem and current treatments are inadequate. We are investigating a novel role for macrophages (cells important in tissue maintenance and immune responses) in bone growth, repair and disease. Greater understanding of this will provide new ways to treat bone disease. We will also determine if these macrophages help support stem cells that reside near bone surfaces, which may provide new treatment strategies to improve bone marrow transplantation in cancer.
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
Understanding Skeletal Development: A Non-proteolytic Mechanism Of Aggrecan Resorption In The Growth Plate
Funder
National Health and Medical Research Council
Funding Amount
$563,044.00
Summary
Bone formation requires resorption of a cartilage template. We challenge the dogma that cartilage resorption is only by PROTEASES, and propose instead that GLYCOSIDASES might also be involved. Aims: Demonstrate that chondrocytes release glycosidases that are important for bone formation. Significance: New information for the design of reconstructive therapies for people with congenital and acquired limb deficiencies or inherited disorders such as arthritis and chondrodysplasias may be gained.
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