The Molecular And Cellular Mechanisms Responsible For The Skeletal Complications Associated With Multiple Myeloma.
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened activation of recruitment of osteoclasts. Osteoclasts are cells ....Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened activation of recruitment of osteoclasts. Osteoclasts are cells which normally, in a controlled manner, resorb bone as part of the ongoing process of new bone formation. We propose that myeloma cells, which exhibit characteristics of osteoclasts, home to sites in the bone marrow and initiate this bone breakdown and furthermore secrete factors required for osteoclast maturation and activity. We believe that these molecules include the recently defined molecule, termed osteoclast differentiation factor, which is normally produced by bone-producing cells known as osteoblasts. Moreover, we feel that myeloma B cells alter the function of osteoblast cells, which results in a decrease in bone formation. Finally, we propose that this disease and its associated bone defects originate from changes in the expression of a number of genes. The results from theses studies should provide a greater understanding of the way in which this B cell cancer originates and how it causes bone defects. This will lead to the development of better treatments to improve the survival of patients with MM, and will lead to therapies to prevent the associated bone complications.Read moreRead less
The Role Of CXCL12 (SDF-1)/CXCR4 In Pathological Angiogenesis And Osteolytic Bone Disease In Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$665,896.00
Summary
Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine mol ....Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine molecule called CXCL12 which acts as a calling card for plasma cells to leave the lymph node and migrate to the BM. Once within the BM, the cells rapidly grow in response to BM-derived growth factors. This rapid growth causes a depletion in oxygen availability within the tumour and it becomes hypoxic. In response to this hypoxia, the tumour expresses a gene called hypoxia-inducible factor-1 (HIF-1) which regulates the expression of many proteins, including the chemokine CXCL12. Our studies show that the abnormal expression of CXCL12 by the plasma cells acts to promote blood vessel formation within the tumour, which in turn leads to greater tumour growth. In addition, our studies suggest that abnormal CXCL12 expression also promotes the recruitment and activation of large numbers of osteoclast (OC) precursors form the peripheral blood. OC are cells which normally remove unwanted or damaged bone. This proposal will study the interplay between HIF and CXCL12 in the establishment and development of MM and the associated bone destruction.Read moreRead less
Molecular And Cellular Mechanisms Of Skeletal Disease Mediated By Plasma Cell Dyscrasias
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in add ....Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.Read moreRead less
Determining The Influences Of Cell Stress And Heat Shock Factor-1 Action In Osteoclast Formation And Pathological Bone Loss.
Funder
National Health and Medical Research Council
Funding Amount
$657,287.00
Summary
Cancer and rheumatoid arthritis cause painful bone destruction. This occurs due to increased numbers of bone destroying cells called osteoclasts. We found stress responses in bone cells can increase osteoclast numbers by activating proteins inside the bone cells that encourage osteoclasts to form. We will thus study whether cell stress blocking drugs might stop bone loss. As arthritis and cancer both cause stress responses, this work could identify a new way that such diseases affect bone.
I am an orthopaedic surgeon and clinician-scientist based at Sydney’s largest children’s hospital. My goal is to improve treatments for children with traumatic injuries and bone deformity. I have worked in bone research for over 20 years. My current research interests are finding new treatments for drug-resistant bacterial infections, treating genetic bone disease, and developing new medical devices to help children’s bones grow straight.
Sclerostin: A Key Regulator Of Bone Mineralisation And Bone Catabolism
Funder
National Health and Medical Research Council
Funding Amount
$536,653.00
Summary
The regulation of bone mass is critical for many areas of human disease including osteoporosis, osteoarthritis, inflammatory bone loss conditions, e.g. rheumatoid arthritis, cancers of bone and problems relating to orthopaedic prosthesis failure. The osteocyte, the most abundant bone cell, plays a central role in normal bone biology and is likely key to these diseases. Sclerostin is one osteocyte product that may be a key to understanding how boneÍs mass and composition is controlled locally.
This study aims to identify naturally occurring genetic variations between men which modify the impact of testosterone, the major male hormone, on men's health and medical care. This study will examine new factors which determine how much any particular man may gain benefit from testosterone exposure such as in muscle and bone development as well as suffer detrimental effects on cardiovascular and prostate diseases. This may clarify some new aspects of how men's health is determined as well as d ....This study aims to identify naturally occurring genetic variations between men which modify the impact of testosterone, the major male hormone, on men's health and medical care. This study will examine new factors which determine how much any particular man may gain benefit from testosterone exposure such as in muscle and bone development as well as suffer detrimental effects on cardiovascular and prostate diseases. This may clarify some new aspects of how men's health is determined as well as developing new, customized medical treatments for men.Read moreRead less
Delayed bone healing can be a considerable problem in both children and adults. Up to 10% of fractures fail to heal properly. An advanced understanding of the cellular responses in bone repair and their manipulation could improve the lives of many patients with orthopaedic problems. These studies will advance out knowledge of interventions to promote bone healing which could be translated rapidly into clinical care.
The Central Role Of The Osteocyte In Skeletal Pathophysiology
Funder
National Health and Medical Research Council
Funding Amount
$638,517.00
Summary
Bone diseases affect more people than any other group, carry a huge and growing socioeconomic cost, yet their aetiologies are not fully determined. This study will elucidate the role of the resident bone cell, the osteocyte, in prevalent bone diseases such as osteoporosis, osteoarthritis and related orthopaedic conditions, rheumatoid arthritis, bone cancer, and in systemic metabolism. The goal is to provide the knowledge and mechanisms for developing improved treatments and patient outcomes.
Osteoblast Control Of Mesenchymal Progenitor Cell Differentiation: The Role Of Glucocorticoids And Wnt Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$443,131.00
Summary
Osteoporosis is an important and growing health issue. Reduced ability to make new bone is an important cause of osteoporosis. In this project we will study how the immature cells which eventually make bone are recruited and controlled. In particular, we will study how genes coding for important growth factors are regulated so that the proper signals are sent to young cells to induce them to become bone-making rather than fat-making cells.