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
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.
Experimental And Computational Study On Biomechanical Behavior Of Osteocytes
Funder
National Health and Medical Research Council
Funding Amount
$86,073.00
Summary
The experimental and computational methods (finite element method) are used to predict biomechanical behaviors of osteocytes under normal physiological loading, overloading or under-loading/disuse. This quantitative research will not only help to elucidate the mechanisms of mechanotransduction in osteocytes, it will provide important information that is also relevant to mechanobiology in general.
The osteocyte, the most abundant bone cell, likely plays a central role in bone biology and diseases, such as osteoporosis. The osteocyte product Sclerostin is a key regulator of bone mass. We are characterising novel pathways of sclerostin action via the expression of microRNAs.
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.
Menopause is one of the important risk factors for bone loss, structural decay and bone fragility. We aim to quantify the biochemical, microstructural and biomechanical basis of loss of bone strength during and after menopause. A cohort of 324 pairs of female-female twins aged 25 to 75 years old will be followed up for up to 9 years. Defining the structural basis of bone fragility provides a rational means to identifying women at risk for fracture.
Does Teriparatide Reverse Osteonecrosis Of The Jaw In Patients With Cancer? A Randomised, Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$137,700.00
Summary
Osteonecrosis of the jaw (ONJ) is a debilitating bone condition involving damage and suboptimal healing of bone involving the jaw. This has been associated with bisphosphonate therapy, which is commonly used for the treatment of both cancer and osteoporosis. My research aims to investigate the role of recombinant parathyroid hormone in the stimulation of bone formation and healing and, thus, its potential to reverse ONJ.
Influence Of Osteocytes On Anabolic Bone Therapies
Funder
National Health and Medical Research Council
Funding Amount
$586,965.00
Summary
This project seeks to define the influence of changes in gene expression in cells called osteocytes, that exist within the substance of bone. These cells form a communication network within the bones of the skeleton, and appear to influence bone formation; changes in gene expression by these cells could influence the efficacy of current and emerging osteoporosis therapies.
The Effects Of Zoledronic Acid On Bone Architecture In Premenopausal Women With Breast Cancer Receiving Adjuvant Combined Ovarian Suppression And Aromatase Inhibitor Therapy: A Randomised Controlled Trial.
Funder
National Health and Medical Research Council
Funding Amount
$122,714.00
Summary
In premenopausal women, a new treatment method that reduces oestrogen levels to almost zero significantly reduces the risk of breast cancer recurrence. However, this is likely to cause substantial bone loss leading to fractures. Using a new imaging technique (HR-pQCT), the effects of profound oestrogen deprivation on bone structure in premenopausal women will be studied. The ability of zoledronic acid, a drug that reduces bone loss, to prevent these adverse bone effects will also be examined.