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Developing a Fully Human 3D Bone Organ Model of Paget’s Disease 

On hearing the news that the Paget's Association had approved funding for their Paget's research Professor Hulley, from the Botnar Research Centre at the University of Oxford, said, “Thank you!! This is very good news. It means a great deal to us to be able to develop our system in this way to be more helpful to patients. We are enormously grateful to the Paget’s Association for their interest and vision!”. 

Professor Philippa Hulley and Dr Helen Knowles summarise their fascinating new project below. 

"Paget’s disease affects all three specialist bone cells that work together to engineer the mechanical architecture of human bones. These cell types are osteoblasts that build bone, osteoclasts that break it down and osteocytes that form a long‑lived residential network, locally co‑ordinating the work of the other two cells. Paget’s causes focal loss of bone where the osteoclasts become aggressively active and erode bone excessively and the osteoblasts fail to repair these weakened patches properly. This suggests a focal loss of control that is likely to come from the osteocytes because they live the longest of all the bone cells and provide a locally co‑ordinated response to damage or changes in loading. The most common disease‑causing mutation in Paget’s disease is in a gene called SQSTM1 and our goal is to investigate, for the first time, how this mutation affects the regulatory/co‑ordinating role of the osteocytes. 

Osteocytes are notoriously difficult to grow in the lab and, since Paget’s is a human disease, mouse models are limited in predicting mechanisms and responses to treatment. However, we recently discovered how to make human osteocytes from donated bone tissue, scraps of “sawdust” leftover from cutting or drilling when knees and hips are replaced. We can grow the bone cells over several months in statically loaded, 3D mini‑bone constructs that move through the adult bone formation process until mature osteocytes emerge. Using this technique, for the first time, we can investigate the effect of Paget’s mutations in human osteocytes and discover what these master cells do in Paget’s disease. 

Furthermore, we recently discovered a new way to grow human osteoclasts from donated blood that allows us to handle large quantities of these fragile giant cells. Crucially, we can viably sort them using their cell surface proteins into sub‑groups at different life stages that may be differentially affected by the mutated osteocytes in Paget’s disease.

We now seek to combine both of these new cell systems to fully explore the role of osteocytes in Paget’s disease, modelling standard drug treatments and introducing a common Paget’s mutation into the osteocytes to see for the first time what these osteocytes do in Paget’s disease. This model will then be ready to populate with cells derived from donated blood or tissue from patients with Paget’s disease or other rare bone diseases, providing the first‑in‑kind fully human mini‑bone organ disease model. This will provide a uniquely human drug discovery tool for testing novel therapeutics and achieving personalised medicine with customisable use of individual patient’s cells or mutations."

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