Impaired Bone Remodelling Leads To Failure Of Orthopaedic Prostheses
Funder
National Health and Medical Research Council
Funding Amount
$515,917.00
Summary
The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%, meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is becoming more common for young, active in ....The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%, meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is becoming more common for young, active individuals to receive joint replacement surgery to improve their quality of life. This, combined with increasing life expectancy, and the known higher rate of failure of joint replacements in younger patients, means that the morbidity of a failed replacement, and the mobidity and associated mortality of revision surgery, will become an increasingly important health issue, with a major impact upon health budgets. The overwhelming majority of hip and knee prostheses have metal or ceramic on polyethylene bearing surfaces. It is now apparent that most implants fail due to bone loss around them leading to loosening, and evidence is accumulating that polyethylene wear particles are a major contributing factor to this process. It is therefore vital that we obtain better understanding of the causes of implant failure in order to extend the life of these implants and this project is designed to do so.Read moreRead less
Molecular And Histopathological Investigation Of Stress Fracture Healing And Effects Of Anti-inflammatory Drugs.
Funder
National Health and Medical Research Council
Funding Amount
$412,652.00
Summary
Stress fractures are debilitating injuries affecting children, adolescents and adults in sport, and army recruits. They also occur in horse and greyhound racing, often resulting in euthanasia of the animals involved. They incur considerable costs in medical expenses, time lost from sport and interruption to military training. But, there is almost no information on the mechanism of healing of these fractures. Non-steroidal anti-inflammatory drugs (NSAIDs) are still the most widely used medication ....Stress fractures are debilitating injuries affecting children, adolescents and adults in sport, and army recruits. They also occur in horse and greyhound racing, often resulting in euthanasia of the animals involved. They incur considerable costs in medical expenses, time lost from sport and interruption to military training. But, there is almost no information on the mechanism of healing of these fractures. Non-steroidal anti-inflammatory drugs (NSAIDs) are still the most widely used medication in management of musculoskeletal injuries, yet their effect on healing of stress fractures is unknown. NSAIDs delay fracture healing, but until recently there has been no standardised way of studying stress fractures. We have created, for the first time, a well-characterised, non-invasive model of stress fractures in the forearm of rats that closely resembles the clinical situation. This provides a novel and unique opportunity to determine the histological and molecular mechanism of stress fracture healing, and to investigate effects of antiinflammatory-analgesic medications on this process. Rats will have an experimental stress fracture produced in one forelimb, and its healing will be examined up to ten weeks using microscopic investigation and analysis of the genes that are turned off or on to initiate the process. Groups of rats will also be treated with antiinflammatory drugs such as ibuprofen, specific COX-2 inhibitors and a new class of drugs that target early immune responses called C5a receptor antagonists. The analgesic Paracetamol will also be investigated as an alternative to the NSAIDs described above. There is widespread use of anti-inflammatory agents in managing stress fractures, so it is vital that their effects on stress fracture healing be examined. This project has enormous significance for optimising approaches for clinical management of stress fractures and for understanding the interaction of anti-inflammatory or analgesic agents in that process.Read moreRead less
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
The Role Of Suppressor Of Cytokine Signalling-3 (SOCS-3) In Chondrocytes During Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$348,392.00
Summary
Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced ....Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced by a wide range of stimuli, especially from a group called the IL-6 family. We have preliminary data showing that cartilage cells (chondrocytes) normally produce a particular SOCS protein, called SOCS-3. We have also shown that when SOCS-3 production is dysregulated, the chondrocytes undergo excessive proliferation. Normal chondrocyte function is important during skeletal development and diseases such as osteoarthritis are thought to result from abnormal chondrocyte behaviour. It is likely that SOCS-3 has a key role in regulating chondrocyte function. The aim of this proposal is therefore to examine the role of SOCS-3 in chondrocytes, during development and in disease. Much of our understanding of the role of the SOCS proteins comes from the construction of mutant mice that lack a particular SOCS protein. When mutant mice are made that lack SOCS-3 in the whole animal the mice die before birth and so virtually nothing is known about the role of SOCS-3 in chondrocytes and the implications for cartilage in disease states, such as arthritis. To answer this we will create mice that lack SOCS-3 specifically in their chondrocytes. Evaluating the role of SOCS-3 in cartilage development and chondrocyte function during degenerative and inflammatory disease states is potentially of major clinical importance in improving our understanding of arthritis and of cartilage repair.Read moreRead less
Roles Of Injury-induced Inflammatory Response In Regulating Bony Repair At Injured Growth Plate Cartilage
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play, trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to 30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth defects result from bony repair of the injured growth cartilage, w ....Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play, trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to 30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth defects result from bony repair of the injured growth cartilage, we largely don't understand why and how this bony repair occurs. Understanding mechanisms for this faulty bony repair of injured growth plate will be critical prior to effective biological treatments can be developed. Recently, using an injury model in young rats, we found that bony tissue formation at injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses. The inflammatory response is an initial event and our recent studies suggest that inflammatory response recruits inflammatory cells and produces important molecules that could significantly influence subsequent fibrogenic, chondrogenic and osteogenic events leading to the bony repair of the injured growth plate cartilage. The current proposal further addresses roles of the inflammatory response and the molecular pathways of this response in regulating downstream bony repair events. This project will generate novel understanding on the faulty bony repair of injured growth plate, and will provide valuable information for developing cost-effective and simple therapeutic intervention that aims to prevent bony repair and to enhance cartilage regeneration of the injured growth plate in children.Read moreRead less