From ageing to space travel: Developing an organotypic model of skeletal tissue disuse for understanding degeneration in altered environments

A substantial loss of skeletal tissue takes place in several clinical contexts, including disuse osteoporosis, ageing and weightlessness in microgravity, all characterised by rapid and significant loss in bone mass in the load-bearing regions. This increases the risk of fractures and places a significant burden on the healthcare system due to the costs associated with interventions.

While bone mass is known to decrease proportionally with reduced loading, the cellular processes governing it require further understanding. There are relevant animal models available that involve surgical excision of glands, immobilisation using toxins, surgical resection, or tail suspension facilitating hindlimb unloading. Some of these processes are very detrimental and others interfere with systemic signalling pathways. Moreover, the translation of findings to human applications is difficult, due to differences in bone remodelling between species and between strains of the same species.

The aim of this work is to produce a physiologically-relevant model that can reduce the number of animals used for understanding skeletal degeneration. Specialised human skeletal cells will be cultured inside spheroidal human-derived fibrin scaffolds within a low-shear, low-load culture system. Mechanical unloading will be simulated using rotary culture bioreactors that keep the cells in a constantly suspended state. Foundation work showed that these templates can provide a degree of support, whilst allowing bone cells to replace them with a collagenous matrix, which becomes mineralised with lacunar structures inside it.

This model will aid studies of early bone loss processes which are essential for understanding disuse pathology. It will also provide a first-stage elimination step for identifying toxic and incompatible compounds, before progressing to in vivo testing, accelerating the search for novel drug formulations and therapeutics.

• News item: Replacing animal models of bone degeneration and disuse with a micron-scale organoid
• Further Funding: NC3Rs Skills and Knowledge Transfer grant, The application of trabecular bone organoids to investigate mineral-sensing in skeletal physiology and disease, June 2022, £72,356 
• Engagement Activities: Pint of Science 2019