The application of trabecular bone organoids to investigate mineral-sensing in skeletal physiology and disease

Bone performs essential endocrinological functions by interacting with several calciotropic organs (parathyroids, kidneys and the gut) to regulate calcium and phosphate homeostasis, under the control of the parathyroid hormone and mediated through the calcium sensing receptor (CaSR). Because of the complexity of the signalling routes involved, disorders of mineral metabolism can often occur. Understanding these pathologies is essential for developing novel therapeutics, many which have failed clinical trials. Currently, studying these processes relies on animal models, which require surgical interventions or genetic alterations to remove essential components in bone formation. Mice strains are frequently used around the world, however, they are too complex to allow the isolation of individual organ-level effects. Previous NC3Rs-funded work conducted by Dr Alexandra Iordachescu (University of Birmingham), allowed the development of a model of mature bone in vitro for the first time, where mineral and cells could be monitored over physiologically-relevant periods (up to one year and beyond). Subsequently, through further NC3Rs funding, Dr Iordachescu miniaturised this model into an organoid system which behaved as a complete remodelling unit and was suitable for larger-scale pharmacological testing. At the same time, recent work from Dr Donald Ward's lab (University of Manchester) identified the CaSR as a phosphate sensor, explaining how excessive circulating phosphate worsens secondary hyperparathyroidism in chronic kidney disease (CKD). Because the CaSR is also expressed in bone cells, where it is involved in repair and maturation processes, it is essential to determine the specific effects of phosphate and therapeutics on the bone CaSR. Therefore, a bone model is required that is isolated from circulating calciotropic factors but possesses native features and capacity for mineralisation, a challenge perfect for these bone organoids and which would reduce the need for rodent models.