Relationship Of The Anabolic And Catabolic Responses In Healing A Critical Sized Defect In Rats
Funder
National Health and Medical Research Council
Funding Amount
$329,750.00
Summary
Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bon ....Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bone resorbing response, the catabolic response, may be too high and prevent healing from occurring. In normal bone healing, there is a balance between the anabolic and catabolic response. In disordered bone healing, these responses are out of balance. Several reasonably new treatments are available which can increase the anabolic response or decrease the catabolic response. We have preliminary results showing that with these agents we can bring these elements into better control, and thus drive bone healing. We have optimised an animal model where both the anabolic and catabolic responses can be controlled. In this project, we explore the optimisation of the timing and magnitude of anabolic and catabolic responses in bone healing.Read moreRead less
Preclinical Optimisation Of Intrauterine Transplantation Of Fetal Mesenchymal Stem Cells For Osteogenesis Imperfecta.
Funder
National Health and Medical Research Council
Funding Amount
$600,932.00
Summary
Osteogenesis imperfecta is a genetic disorder causing brittle bones and fractures. Currently there is no good treatment. Transplanting stem cells before birth should allow them to build healthy bones early in life. Despite promising effects in animals, stem cell uptake is too low to prevent all fractures and ameliorate pain and deformity. We are studying how to improve the uptake of stem cells given to the fetus and neonate, in order to develop a treatment suitable for eventual use in humans.
This project is a biochemical investigation of collagen, which is the principle protein of bone, joints, blood vessels and skin. More than 200 mutations have been identified in the genes for type I collagen that result in Osteogenesis Imperfecta (OI), otherwise known as brittle-bone disease, in children and adults. However, very little is known about how these mutations cause bones to be brittle and why the disease varies so widely in severity. Our experiments are directed towards a better under ....This project is a biochemical investigation of collagen, which is the principle protein of bone, joints, blood vessels and skin. More than 200 mutations have been identified in the genes for type I collagen that result in Osteogenesis Imperfecta (OI), otherwise known as brittle-bone disease, in children and adults. However, very little is known about how these mutations cause bones to be brittle and why the disease varies so widely in severity. Our experiments are directed towards a better understanding of how bone cells respond to the mutant collagen and how these mutations actually result in brittle bones. We know that the majority of OI-causing mutations typically lead to a severe OI because the mutant collagen interferes with normal functioning of the matrix and effectively weakens it. We will examine how the mutant collagen disrupts normal cell function using bone and skin cell lines in which we have added a mutated collagen gene. The mutations we will introduce are the same ones that cause OI in patients. The experiments cannot be carried out with OI cell lines isolated from humans because it is very difficult to identify the mutant collagen in the matrix. Instead we have engineered a marker into the mutant collagen to allow the mutant collagen to be easily tracked. We will then examine how the presence of the mutant collagen affects matrix integrity, turnover and the formation of mutant matrix. In the second part of the study we will make a transgenic mouse that carries a specific collagen mutation. This will allow us to examine the fate of mutant collagen in a whole animal. As with the engineered cells described above, the mutant collagen will be altered to allow easy tracking. Collectively, these experiments will provide valuable information about how the presence mutant collagen disprupts integrity of the extracellular matrix of skin and bone.Read moreRead less
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.
Molecular Mechanisms Of Collagen Matrix Assembly In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,171,996.00
Summary
This project studies the way the specific protein building blocks of tissues interact with each other to form the complicated structural networks necessary for tissue growth, development and function. Specifically, we will study collagens, the main structural proteins of the body. We will determine how they assemble with other proteins to form the complex fibrils or molecular ropes, which provide mechanical strength to tissues and create the environment for cells to grow and develop in tissues s ....This project studies the way the specific protein building blocks of tissues interact with each other to form the complicated structural networks necessary for tissue growth, development and function. Specifically, we will study collagens, the main structural proteins of the body. We will determine how they assemble with other proteins to form the complex fibrils or molecular ropes, which provide mechanical strength to tissues and create the environment for cells to grow and develop in tissues such as bone, skin, cartilage and muscle. We will explore the effect of collagen mutations, that occur in patients with inherited diseases of cartilage and muscle, on these assembly processes. This will provide key information on the disease process, so that in the future new approaches to diagnosis and therapy can be developed. The understanding we gain on the molecular basis of tissue structural assembly from these studies will be of importance for understanding normal tissue growth and development, and for the development of new biomaterials for therapeutic use.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
Role Of The Osteoclast In Endochondral Fracture Repair
Funder
National Health and Medical Research Council
Funding Amount
$310,136.00
Summary
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 successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone resorbing cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been considered essential to the initial stages of bone repair (endo ....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 successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone resorbing cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been considered essential to the initial stages of bone repair (endochondral ossification) during which the early soft cartilaginous callus is replaced by hard mineralised callus. Our preliminary studies lead us to believe that endochondral ossification can indeed proceed without osteoclast activity. If we can safely eliminate osteoclast function early in the early stages of fracture repair, a number of therapeutic options open up for the augmentation of bone healing. The return of osteoclast function is necessary in the long term, so our strategy will also need to take this into account. This study will establish which systems are pivotal in endochondral ossification and therefore which interventions we should explore.Read moreRead less
Peptides Bound To Commonly Used Orthopaedic And Dental Biomaterials:In Vitro And In Vivo Effect On Osteogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$273,428.00
Summary
In 1992, the orthopaedics industry fitted some 300,000 prosthetic devices, artificial hips, knees, giving this industry a global market of $2.1 billion with a projected market growth exceeding 10% per annum. In (1994-5) 5,717 prosthetic hips and 4,593 knees were surgically implanted in NSW of which 14% of hips and 9.5% of knees were revisions. Considerable health funding is allocated to joint replacement for the nation, although successful, outcomes are finite. Importantly, and aside from costs, ....In 1992, the orthopaedics industry fitted some 300,000 prosthetic devices, artificial hips, knees, giving this industry a global market of $2.1 billion with a projected market growth exceeding 10% per annum. In (1994-5) 5,717 prosthetic hips and 4,593 knees were surgically implanted in NSW of which 14% of hips and 9.5% of knees were revisions. Considerable health funding is allocated to joint replacement for the nation, although successful, outcomes are finite. Importantly, and aside from costs, patients morbidity is high. The major cause of long-term failure of these prosthetic replacements is aseptic loosening, the result of bone loss at the bone-device interface. Novel approaches to development of more efficient implant materials would ultimately lead to major contributions to the mobility and and quality of life for these patients. Considerable effort has been devoted to alter surface characteristics of orthopaedic implants to improve the interlocking of device and skeleton. We were the first to demonstrate that surface chemical modification of biomaterials using selected ions resulted in an enhanced bone formation. This proposal is aimed at chemically modifying the surfaces of commonly used orthopaedic and dental materials, to improve the biocompatibility of new devices and the surface coatings for existing prostheses. Furthermore, this application will build on the in vitro data showing that particular peptides specifically bind osteoblasts and therefore have the potential to provide a surface on a prosthesis that is conducive to bone formation. To date, we have coupled these peptides to metallic surfaces and will proceed to study the osteoblastic phenotype and subsequent osteogenesis. Development of these novel biocompatible surfaces is anticipated to reduce patient morbidity and result in significant health care savings.Read moreRead less