Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosi ....Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosis.Read moreRead less
Molecular Mechanisms And Therapeutic Effects Of Novel Parthenolide Analogs On Osteolysis
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Rheumatoid arthritis and osteoporosis are common bone diseases with features of bone loss. Drugs that inhibit bone loss are needed for the prevention and treatment of bone diseases. The proposed research explores the potential use of novel herbal inhibitors for the suppression of bone resorbing cells, and their potential as treatments for bone loss.
Furin: Carving-up Vital Substrates For Bone Remodelling And Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$815,972.00
Summary
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. It is caused by an imbalance between the cells that are constantly reabsorbing and reforming bone. The proposed project will address furin as a novel regulator of bone remodelling.
The Effect Of Weight Loss On The Risk Of Knee Osteoarthritis And Potential Modification By Biomechanical Factors
Funder
National Health and Medical Research Council
Funding Amount
$475,388.00
Summary
Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life. This has been acknowledged by its listing as the 7th health priority in Australia. Knee OA is the most common reason for a joint replacement, thus imposing a huge financial burden to the community. Treatments which slow-prevent OA progressioning are limited and so prevention must play a key role. Obesity is the most significant, potentially modifiable risk factor for knee OA. The combinati ....Osteoarthritis (OA) has the largest impact of any chronic disease on burden of disease borne in later life. This has been acknowledged by its listing as the 7th health priority in Australia. Knee OA is the most common reason for a joint replacement, thus imposing a huge financial burden to the community. Treatments which slow-prevent OA progressioning are limited and so prevention must play a key role. Obesity is the most significant, potentially modifiable risk factor for knee OA. The combination of the current epidemic of obesity in Western countries and the aging of the population is likely to have a synergistic effect on the prevalence and incidence of knee OA. Despite the consistent relationship between obesity and OA, little work has been done on the relationship between obesity and biomechanical factors such as knee angle and muscle mass and how these may interact with obesity and weight loss in modifying the risk of knee OA. It may be that weight loss programs could be more effective at reducing the risk of OA if they are combined with programs aimed at correcting muscle weakness and malalignment. This has the potential to promote a better quality of life as people age and to reduce the economic burden of knee OA in the community.Read moreRead less
We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has not previously been possible to accurately exp ....We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has not previously been possible to accurately explore the relationship between prothesis wear and PO, or the progression of PO, because of a lack of techniques to image and measure the volume of PO around metal prosthesis components. We have developed a means to accurately and reproducibly measure the volume of bone loss, using CT, and will do so longitudinally in joint replacement patients to obtain the first information about the progression of PO. New computer based methods will be used concurrently to relate prosthesis wear and migration parameters to PO. Patients who come to surgery for replacement of failed prostheses will be investigated further by analysis of the tissues involved in the bone loss around prostheses. Basic science experiments will seek to understand the underlying causes of PO and the findings will be important in interpreting the clinical results. An animal model will be used to seek approaches to inhibiting the pathological response to wear particles. The significance of these studies is that they will lead to improved outcomes for joint replacement patients, increasing the interval to revision surgery, which is both extremely costly and brings an attendant morbidity and mortality.Read moreRead less
Role Of Musculoskeletal Biomechanical Factors In Cartilage Loss In Those Who Undergo Partial Medial Menisectomy.
Funder
National Health and Medical Research Council
Funding Amount
$654,530.00
Summary
The novel outcomes from our project are that we will identify whether musculoskeletal-biomechanical factors that can be modified are associated with adverse cartilage changes in a subgroup of individuals with an increased risk of developing knee OA, those who have undergone an APM. The findings of this research are timely and of major international significance as there is increasing attention being paid to preventing OA rather than merely treating the signs and symptoms. Our state-of-the-art me ....The novel outcomes from our project are that we will identify whether musculoskeletal-biomechanical factors that can be modified are associated with adverse cartilage changes in a subgroup of individuals with an increased risk of developing knee OA, those who have undergone an APM. The findings of this research are timely and of major international significance as there is increasing attention being paid to preventing OA rather than merely treating the signs and symptoms. Our state-of-the-art measure of cartilage changes will allow us to detect those at risk much sooner than traditional measures using radiographs. The measures are also leading edge internationally. We chose these specific factors to investigate as there is evidence that they can be modified with appropriate interventions. For example, static joint alignment could be modified with foot orthoses [Crenshaw, 2000 #1016], muscle weakness can be addressed with strength programs and mechanical loading across the knee could be reduced via weight loss programs or techniques to alter gait patterns. Currently, formal supervised post-operative rehabilitation is not routinely prescribed following APM because it is considered a routine procedure. If our research identifies risk factors for increased cartilage loss then we will be able to develop appropriate intervention strategies for individuals following an APM. These interventions can then be formally tested as to their effectiveness in reducing adverse cartilage changes using randomised controlled trials. In particular, this could lead to changes in current post-operative clinical practice for this patient group. Ultimately, this could reduce the risk of OA in the future and the resultant personal and societal costs of this condition.Read moreRead less
V-ATPases Subunit D2 Is Critical For Acdification And Bone Resorption.
Funder
National Health and Medical Research Council
Funding Amount
$531,264.00
Summary
Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, aci ....Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption. Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast function and bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone disordersRead moreRead less
The Role Of CHKB In Osteoclastic Bone Resorption And Bone Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$565,695.00
Summary
Osteoporosis is a devastating disorder. Osteoporotic fractures in the elderly have been correlated with increased mortality rates. Osteoporosis alone costs $13.8 billion p.a. in USA and tens of millions of dollars in Australia. Cost to society of our ageing population for people become disabled by hip fractures alone could triple by the year 2040. Our research examines the role of CHKB in bone loss which may underscore its potential as a new molecular target for anti-resorptive drug development.
Heat Shock Transcription Factors In Bone Remodeling And Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,427.00
Summary
The denisity of bone is finely balaned and required for a healthy lifestyle. During times of disease, damage or drug treatments the bone can be compromised, often decreasing in density and becoming fragile. This often leads to fractures, pain and a poor quality of life. This proposal seeks to investigate whether stress insults to bones plays a role in the loss of bone. This will provide new insights into bone loss during disease and lead to novel treatment strategies.
Interrelationships Between The Disc And Bone Of Lumbar Spinal Segments
Funder
National Health and Medical Research Council
Funding Amount
$423,625.00
Summary
The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal degeneration includes disc degeneration, facet joint osteoarthritis, ....The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal degeneration includes disc degeneration, facet joint osteoarthritis, compromised vertebral body bone quality, muscle and ligament alterations. It is assumed that these changes result in increased or abnormal spine motion and modified load distribution across the spinal joint. It has been found that with age, there is increased disorganisation of the intervertebral disc and decreased quality of vertebral cancellous bone. However, bones with the same density within the range of normal subjects, can show selective loss of bone structure and reduced load-bearing capacities of these vertebrae. An important concept here is that even for a given bone mass, fracture risk increases with age, supporting the view that there is a component of bone fragility that is independent of mass. Increased bone fragility may be associated with compromised cancellous bone structure. While the relationship between disc degeneration and changes in vertebral bone is commonly invoked, the mechanisms of this relationship have largely been overlooked, with age changes given more attention. However, it may be that intervertebral disc disorganisation modulates age-related bone changes within the spine. Disc degeneration may influence trabecular bone responses before changes with age put the patient at risk of vertebral crush fracture. We propose that the mature disc cannot effectively regenerate after damage, and thus responses to disc damage will be more readily observed in vertebral bone architecture than in the disc.Read moreRead less