Molecular Determinants Of Bone Remodelling In The Bone Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$317,640.00
Summary
There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, t ....There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and histomorphometric studies will determine whether the understanding derived from tissue culture and animal experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The elucidation of the molecular signalling in the human bone microenvironment is essential for the effective diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data shows that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further investigate mRNA gene expression of a number of cytokines involved in bone cell signalling and their association with the level of microdamage in the bone. Using a animal model of controlled bone microdamage induction we will seek to determine the bone remodelling causal relationship between microdamage and cytokine signalling. Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are not well understood. These studies will provide new insight into the processes that determine trabecular structures. This project will investigate these mechanisms and increase our understanding of bone cell function, essential for diagnosis and design of rational treatment for bone diseases.Read moreRead less
Osteoporosis is a disease associated with a progressive rise in the number of fractures in the elderly. These fractures are so common that around 1 in 3 women and 1in 4 men will be affected. They cause pain, disability that can be permanent and are associated with loss of independence even premature death. Current treatments are able to partially restore bone strength in osteoporotic patients but can not return bone strength to normal. Some new treatments can restore bone strength to some extent ....Osteoporosis is a disease associated with a progressive rise in the number of fractures in the elderly. These fractures are so common that around 1 in 3 women and 1in 4 men will be affected. They cause pain, disability that can be permanent and are associated with loss of independence even premature death. Current treatments are able to partially restore bone strength in osteoporotic patients but can not return bone strength to normal. Some new treatments can restore bone strength to some extent but these are limited by expense and safety concerns. We have discovered a pathway in the brain that when blocked, results in a doubling of the amount of bone in key bone sites and dramatic increases in bone strength. This occurs due to a marked increase in the amount of new bone formed. In fact, genetic manipulation of this pathway was able to double the speed at which bone is made by the skeleton. Excitingly, these increases in bone were possible in adult mice, suggesting such changes could be potential therapy for human patients. We went on to test the effectiveness of this pathway in animal models of human skeletal weakness and have shown that it is capable of remarkable benefits. However, in order to be able to harness this pathway we must understand what molecules within the bone that are responding to the signals from the brain. Our proposal aims to identify the nerve signalling molecule(s) and pathways for these signals within the bone that initiate the increase in bone formation. This project ultimately aims to identify a target for new therapies that could achieve this beneficial effect by administration in osteoporotic women and menRead moreRead less
Intrinsic Bone Qualities In Fragility Fracture Patients: Mass, Microarchitecture, Mineralization And Damage Accumulation
Funder
National Health and Medical Research Council
Funding Amount
$447,027.00
Summary
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detec ....Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of bone is of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength and fracture toughness (work to fracture) reduce considerably with age. This proposed study would seek to elucidate the role of bone tissue-level properties in determining bone quality for human subjects: patients with fragility hip fractures on no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies, and normal age- and sex-matched individuals. Our laboratory has extensive experience in the analysis of the structure of human bone tissue. Recently, we have developed novel and unique techniques to assess bone quality, using micro-CT, backscatter SEM imaging, confocal microscopy and immunohistochemistry. This multifaceted study will identify at the bone tissue-level the structural mechanisms (micro-architecture, mineralisation, and microscopic cracking) that are indicative of the efficacy of fragility fracture drugs. Better understanding of the mechanisms by which bones are less likely to fracture will enable better targeting of osteoporosis drug therapy to individuals at risk of fragility fracture.Read moreRead less
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
Is Periosteal Bone Formation Responsible For Sexual Dimorphism In Bone Fragility
Funder
National Health and Medical Research Council
Funding Amount
$316,320.00
Summary
Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures more often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of bone is greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is likely that men and women lose a similar amount of bone, about half what they started with, but during ageing, men lay down more bone on the outside surface of the bone than w ....Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures more often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of bone is greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is likely that men and women lose a similar amount of bone, about half what they started with, but during ageing, men lay down more bone on the outside surface of the bone than women compensating for the similar amount lost on the inside of the bone. We also have evidence to suggest than men and women who get spine fractures do so because the process of laying down bone may fail to occur normally. We will study these processes of bone loss inside the bone and bone gain outside the bone to try to better understand why bones become weak. We will measure the bone size and its density in healthy men and women and patients with fractures to determine how the increasing size of the bone produced by laying down bone on its outside helps to keep it strong and to preserve the bone that would otherwise be lost if it didn't occur or if a disease developed that might reduce the compensatoryRead moreRead less
Vertebral Body Strength: Contribution Of Bone Mass, Bone Structure And Material Properties
Funder
National Health and Medical Research Council
Funding Amount
$434,498.00
Summary
This study will determine the contributions to vertebral body strength made by its structural and material properties. Using state-of-the-art computed-tomography scanners, digitised representations of vertebral bodies in three-dimensions will be produced, which enable measurement of bone structure. After strength testing of the vertebral bodies, the structural and material properties, which combine to predict vertebral body strength, will be identified in an aged population.
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in which they work to determine whether they may be good targets for new osteoporosis treatments. We will examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop and function, to determine when the genes are expressed and how they function. We will test the ability of the candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less
The Role Of Genomic Copy Number Variation In Regulation Of Bone Disease Phenotypes
Funder
National Health and Medical Research Council
Funding Amount
$438,600.00
Summary
We have been working to identify quantitative trait loci for key clinical traits relevant to osteoporosis, for the past 15 years, with substantial success. We recently completed a Genome Wide Association Study and identified 20 loci with strong evidence for a role in the regulation of key bone disease phenotypes. In this project we will extend that highly acclaimed research to study genomic copy number variation and define the role of those genetic variants in osteoporosis.
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. No current treatment effectively reverses this bone loss. Using genetic models in mice, we have identified a pathway, involving the nerve signal molecule NPY, that is capable of inducing large (200 - 300%) increases in bone very rapidly (within a few weeks), in the skeleton of adult mice. This proposal is aimed at characterising this new pathwa ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. No current treatment effectively reverses this bone loss. Using genetic models in mice, we have identified a pathway, involving the nerve signal molecule NPY, that is capable of inducing large (200 - 300%) increases in bone very rapidly (within a few weeks), in the skeleton of adult mice. This proposal is aimed at characterising this new pathway to assess its potential to provide new treatments for human osteoporosis. This research is important because of the size, rapidity and inducibility of the effect. Moreover, since it originates in the brain, it represents a quite novel mechanism by which the skeleton is potentially maintained and repaired. The experiments contained in the initial sections of the proposal are designed to assess not only the ability of the NPY-pathway to protect against bone loss but also to examine the possibility of repair to a fragile skeleton. The bone loss models chosen for study represent postmenopausal and age-related osteoporosis, two prevalent and increasingly common conditions in the aging world population. The latter section of the proposal seeks to clarify the mechanism by which the increase in bone formation occurs within the bone. Understanding the working of this pathway will be vital in developing future treatment regimens. This proposal investigates a novel, powerful and rapid pathway for repairing weakened skeletons. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less