Signalling Through A Bioactive Aggrecan Fragment: What Is The Mechanism?
Funder
National Health and Medical Research Council
Funding Amount
$431,347.00
Summary
Osteoarthritis (OA) affects approximately 20% of Australians. There are no therapies that modify the course of the disease and joint replacement surgery is expensive and invasive. We have discovered that a peptide product of cartilage breakdown (the 32mer) signals cartilage cells to mount an inflammatory and catabolic response. We will determine how the 32mer triggers this response, whether other joint cells are similarly activated and how it can be stopped, with the goal of pursuing new targets ....Osteoarthritis (OA) affects approximately 20% of Australians. There are no therapies that modify the course of the disease and joint replacement surgery is expensive and invasive. We have discovered that a peptide product of cartilage breakdown (the 32mer) signals cartilage cells to mount an inflammatory and catabolic response. We will determine how the 32mer triggers this response, whether other joint cells are similarly activated and how it can be stopped, with the goal of pursuing new targets for therapyRead moreRead less
Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better i ....Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better investigate the mechanisms of the bone loss. Drugs to stop the loss of bone have only recently been available to patients and many new treatments are being developed. While most of these drugs are proving useful to treat osteoporosis, their suitability for the treatment of bone loss in diseases such as periodontal disease, rheumatoid arthritis and peri-implant osteolysis is largely unknown. As the way bone is lost in these inflammatory diseases quite different from osteoporosis different treatments are needed. This project aims to better understand bone loss in these diseases and identify new treatments to prevent the debilitating bone loss associated with inflammation in disease.Read moreRead less
The Role Of Perlecan In Tensional Connective Tissues
Funder
National Health and Medical Research Council
Funding Amount
$605,037.00
Summary
Musculoskeletal diseases affect tension and weight bearing connective tissues which have notoriously poor repair capabilities. These conditions are difficult to treat clinically and surgical repair in many cases does not provide a return to optimal joint function impinging on the quality of life of afflicted individuals and their carers. Our project aims to better understand the structure and function of these tissues in health and disease with a view to improving repair strategies.
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
Pathobiology Of The Small Leucine Rich Repeat Proteoglycans In Cartilage, Intervertebral Disc And Tendon Degeneration
Funder
National Health and Medical Research Council
Funding Amount
$516,625.00
Summary
Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common cause of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3 billion) and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million prescriptions. Significant disability due to MSK disease were noted in ~50% of peopl ....Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common cause of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3 billion) and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million prescriptions. Significant disability due to MSK disease were noted in ~50% of people aged 65 years. Australian census data indicates that ageing trends will result in an increased incidence of MSK conditions as the longevity of the Australian population rises, exerting an ever increasing burden on the healthcare budget. Extreme levels of sporting or physical activity from traumatic loading of joints can lead to excessive loading of collagen fibres in MSK tissues leading to their failure and loss of tissue function. Common end stages of collagen fibre breakdown are preceded by matrix changes which may predispose MSK tissues to enzymatic and mechanical damage. One such change is an increased degradation of a family of small leucine-rich proteoglycans (SLRPs) which modulate the diameter, strength and assembly of collagen fibrils and bind and modify the effects of reparative growth factors and degradative cytokines within connective tissues. Altered synthesis of SLRPs and SLRP fragments have been identified in abnormal intervertebral disc, cartilage and tendon. Very little is known however about how these fragments are generated within these tissues and how they affect growth factor binding or collagen fibril formation. This deficiency will be addressed in our proposed study which will provide novel information on mechanisms of cartilage, intervertebral disc and tendon degeneration and potential therapeutic and diagnostic targets which may be exploited in future studies on the treatment of these musculoskeletal conditions.Read moreRead less
Manipulating The Anabolic And Catabolic Responses For Bone Tissue Engineering
Funder
National Health and Medical Research Council
Funding Amount
$58,202.00
Summary
The repair of large bone defects represents a significant clinical problem. Evolving tissue engineering technologies may lead to significant improvements in orthopaedic treatments for these problems. We plan to compare novel biological approaches designed to maximise new bone formation while preventing bone resorption with existing synthetic graft materials. Our research data will be readily translated from the laboratory to a clinical setting.
Cartilage Destruction In Joint Disease: Studies With ADAMTS-4 And ADAMTS-5 Deficient Mice
Funder
National Health and Medical Research Council
Funding Amount
$540,600.00
Summary
In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that ADAMTS-4 and-or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate mice containing mutant ADAMTS-4 and-or -5 in all cells, or [2] in car ....In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that ADAMTS-4 and-or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate mice containing mutant ADAMTS-4 and-or -5 in all cells, or [2] in cartilage cells only. [3] Analyse mutant mice for changes in skeletal architecture, changes in ADAMTS mRNA and protein, and changes in aggrecan breakdown products. [4] Assess disease severity in mutant mice in in vivo models of joint disease. We already have mice with ADAMTS-4, or -5, mutated in all tissues and we are generating the double mutants now. We will also generate single and double mutants with dysfunctional enzymes in cartilage only. We will examine skeletal structure by histology and X-ray at all ages and monitor for expression of ADAMTS-1 and -9 to detect any compensatory over-production of other potential 'aggrecanases'. We will also do co-culture experiments in which cartilage and synovial cells from combinations of mutant and control mice will be incubated together to determine whether synovial ADAMTS can penetrate and degrade aggrecan in cartilage. Finally we will induce arthritis in mutant and control mice and monitor them to detect differences in the time of disease onset, the rate of disease progression and overall disease severity. A comparison of whole-mouse with cartilage only mutants in the in vivo models will complement the in vitro co-culture studies and determine whether other joint tissues such as synovium and joint capsule can also produce ADAMTS enzymes that destroy cartilage. This is not known. Together these experiments will reveal if, where and when ADAMTS-4 and-or -5 are active, and whether indeed they are the best targets for drug development.Read moreRead less
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.