Osteocytes, the most abundant and long-lived, yet least studied bone cell, are increasingly recognised as key controllers of bone remodelling and are implicated in many bone diseases. Our work is uncovering novel molecular and cellular pathways by which osteocytes act and survive in bone, which is generally an oxygen-deprived tissue. This will provide a rational basis to seek improved treatments of bone disease.
Molecular Characterization Of V-ATPase V0 Domain Subunits E1 And E2 In Osteoclast
Funder
National Health and Medical Research Council
Funding Amount
$558,909.00
Summary
Osteoporotic fractures in the elderly are often linked to increased mortality rates. Excess bone resorption is a major contributor to the onset of the disease. The proposed project focuses on the investigation of the molecular mechanisms of acid secretion that is required for the bone degradation in body. The project will examine the role of the proton pump in bone resorption and seek potential targets for the treatment of osteoporosis.
Regulation Of Key Pathways Causing Peri-implant Bone Loss.
Funder
National Health and Medical Research Council
Funding Amount
$403,639.00
Summary
The failure of bone prostheses is becoming a major health problem in our aging population. Despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is now apparent that most implants fail due to bone loss around them which leads to loosening. This project aims to obtain a better understanding of the causes of implant failure and find ways to extend the life of these implants .
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to an increased susceptibility to fractures. Understanding the nature of bone loss may lead to the discovery of a new drug target for the treatment of osteoporosis..
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.
The Role Of Osteocytes In Particle Induced Osteolysis
Funder
National Health and Medical Research Council
Funding Amount
$457,196.00
Summary
Hip replacements often fail due to the loss of adjacent bone. Metal or polyethylene particles are produced as the prosthesis bearing surface wears but how do these particles lead to bone loss? Our work suggests involvement of osteocytes within the bone mineral, which are increasingly understood to drive bone physiology and pathology. We will explore the role of the osteocytes by examining their response to particles, which may identify a new target to prevent particle-induced bone loss.
Targeting The Vicious Cycle Of Cancer-induced Bone Disease With TRAIL And Bisphosphonates
Funder
National Health and Medical Research Council
Funding Amount
$443,696.00
Summary
The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly ....The most serious clinical problem with patients with many forms of solid tumours is metastasis to bone, which leads to potentially debilitating complications that can cause erosion of the patient's quality of life, and eventually death. Unfortunately, bony metastases usually occur before pre-emptive treatments can be applied to prevent it. We have recently shown that recombinant soluble TRAIL is a potent anticancer agent that prevents cancer-induced bone destruction in a mouse model by directly targeting cancer cells within bone, and with no evidence of toxic side effects to normal tissues. Death receptor targeting by TRAIL, and bisphosphonates induce cancer cell apoptosis through different but overlapping signaling pathways. Therefore, combination of the two approaches may facilitate killing of tumour cells that resist death induction through either one of the pathways. Combination therapy may also reduce the probability of acquired resistance to either therapy. We propose that a combinatorial approach, using bisphosphonates to selectively target osteoclasts and TRAIL to selectively target cancer cells, would be an ideal therapeutic and safe approach to delay, slow or completely eliminate growth of cancer within bone.Read moreRead less
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