Orphan Endolysosomal Transporters in Bone Health and Disease

Osteoclasts are giant multinucleated cells responsible for the degradation (resorption) of bone. Excessive osteoclast activity leads to localised bone destruction (osteolysis). Decreased systemic bone mass and fragility fractures are a hallmark of osteoporosis. Conversely, loss of osteoclast function is associated with sclerosing (high bone mass) conditions such as osteopetrosis (also known as ‘stony bone’).

Endolysosomes are specialised membrane-delimited intracellular organelles formed by the fusion of endosomes with lysosomes. They are essential for the bone resorptive function of osteoclasts. Mutations in genes related to the control of endolysosome homeostasis account for most of the known forms of autosomal recessive osteopetrosis in humans.

This project examines the role of previously uncharacterised ‘orphan’ endolysosomal transporters in osteoclast function and their potential involvement in bone disease.

Musculoskeletal diseases represent the third leading cause of disease in the Australian community, showing the need for this project to explore the previously unrecognised pathophysiological role of novel ‘orphan’ lysosomal transporters in bone homeostasis and disease.

This research could prove valuable for the diagnosis of unclassified forms of osteopetrosis and provide novel ‘druggable’ targets for the treatment of osteoclast-related disorders such as osteoporosis.

Associate Professor Nathan Pavlos leads this research project, backed by his knowledge in the Bone field. Associate Professor Pavlos is Head of the Bone Biology and Disease Laboratory at the School of Biomedical Sciences at UWA.

Having completed his PhD studies in Bone Cell Biology at UWA in 2005, Associate Professor Pavlos was awarded a NHMRC CJ Martin (Biomedical) Overseas Research Fellowship in 2007. He then returned to UWA to start his own laboratory with a focus on intracellular trafficking and transport in bone cells.

In collaboration with Professor Jiake Xu from UWA and Professor Rohan Teasdale (University of Queensland) and Robert Parton (Institute for Molecular Bioscience), the research team aims to characterise the role of novel endolysosomal membrane transporters using genetically altered mice as a model organism. Additionally, this project explores the localisation and dynamics of novel membrane transporters at high resolution using optical and electron microscopy techniques. The team has received a National Health and Medical Research Centre grant of more than $675,000 to assist with its research.

PhD opportunities are available for this project for motivated students with an interest and relevant background in molecular biology, biochemistry, cell biology or pathology.

For more information, contact Associate Professor Nathan Pavlos.