The Role Of 'Orphan' Transporters In Bone Homeostasis And Disease
Funder
National Health and Medical Research Council
Funding Amount
$675,668.00
Summary
Osteoclasts (OCs) are giant multinucleated cells exclusively responsible for physiological bone degradation (resorption). Excessive OC activity leads to localised bone destruction (osteolysis) as observed in patients with osteoarthritis and underlies decreased bone mass and fragility fractures that are a hallmark of osteoporosis. This project examines the role of an orphan solute carrier transporter in OC function and its potential involvement in bone disease.
Regulation Of Bone Formation And Resorption By Osteoblastic EphrinB2/EphB4 Signalling
Funder
National Health and Medical Research Council
Funding Amount
$648,479.00
Summary
Skeletal strength is maintained by balanced cycles of bone resorption and bone formation. Cells that live inside the bone matrix, osteocytes, are thought to co-ordinate this. We have found that two proteins, EphrinB2 and EphB4, exist on the surface of osteocytes and regulate bone formation and resorption. This project investigates how they do this, and whether interfering with or enhancing their signals could be used to increase bone strength in osteoporosis.
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.
Myo1b Bridges The Actin-membrane Interface During Osteoclastic Bone Resorption
Funder
National Health and Medical Research Council
Funding Amount
$429,387.00
Summary
Osteoporosis is a debilitating bone disease which features progressive bone loss. Bone loss (resorption) is driven by the bone resident cell the osteoclast. Identifying molecules that regulate bone resorption by osteoclasts is a crucial first step towards developing new targets for theraputic intervention. This proposal explores the role of Myo1b, a novel protein that appears to facilitate osteoclastic bone resorption and thus represents an attractive new candidate to target 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.
Paget's Disease Of Bone Associated Sequestosome 1/p62 Mutations In Autophagy-mediated Processes And Bone Resorption
Funder
National Health and Medical Research Council
Funding Amount
$474,892.00
Summary
Paget’s disease of bone (PDB) is a common, chronic bone disorder characterized by focal lesions of increased bone degradation initiated by giant overactive osteoclasts. Subsequent bone formation is irregular, resulting in bones that are structurally weak. Genetic mutations are a common cause of PDB in Caucasians. Understanding the genetic mutations and their regulation on bone cells may lead to the discovery of a new drug target for the treatment of PDB.
Targeting Histone Deacetylases 1 And 5 To Reduce Inflammation And Bone Loss In Periodontitis.
Funder
National Health and Medical Research Council
Funding Amount
$536,745.00
Summary
Bone loss and tooth loosening are serious complications in periodontitis. Despite the prevalence of this disease current treatments do not directly stop the bone loss. Our recent laboratory studies show inhibiting histone deacetylase (HDAC) activity with very low doses of inhibitors can effectively suppress this bone loss in periodontitis. This project aims to investigate specific targeting inhibitors of HDAC 1 and HDAC 5 to treat periodontitis by enhancing bone formation and reducing bone loss.
IL-6 Classic And Trans-signalling In Bone Physiology And Pathology
Funder
National Health and Medical Research Council
Funding Amount
$731,372.00
Summary
This project seeks to determine whether it is possible to prevent bone loss associated with osteoporosis and inflammatory bowel disease by blocking interleukin 6. Two different methods of blockade will be tested, with the hope that one of these methods will have less side effects.
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.
Osteocytic SOCS3 Controls STAT3:STAT1 Balance And Bone Formation
Funder
National Health and Medical Research Council
Funding Amount
$648,164.00
Summary
The most promising new osteoporosis therapy is antibody-based inhibition of the sclerostin protein. We discovered that sclerostin is inhibited by oncostatin M (OSM) only when it binds to a receptor called LIFR, which then activates proteins STAT3 and SOCS3. If OSM binds a different receptor (OSMR) it increases STAT1 activity and destroys bone. This project will determine how to manipulate STAT3, SOCS3, and STAT1 to increase bone formation and provide new treatments for osteoporosis.