Trabecular bone remodeling in the ageing mouse: a micro-multiphysics agent-based in silico model using cell-type-specific mechanomic profiles

Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. In silico models have been of help to further understand the signaling pathways that regulate the spatial cellular interplay. We have established a 3D multiscale micro-multiphysics agent-based (micro-MPA) in silico model of trabecular bone remodeling using longitudinal in vivo data from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A) mice, a mouse model of premature aging. Our model includes a variety of cells as single agents and receptor-ligand kinetics, mechanotransduction, diffusion and decay of cytokines which regulate the cells’ behavior. The micro-MPA model was applied for simulating trabecular bone remodeling in the CV6 of 5 mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. We identified a configuration of the model parameters to simulate a homeostatic trabecular bone remodeling. Additionally, our simulations showed different anabolic, anti-anabolic, catabolic and anticatabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. From these results, we concluded that OPG inhibits osteoclastic bone resorption by reducing the osteoclast recruitment, RANKL promotes bone resorption by enhancing the osteoclast recruitment and Scl blocks bone formation by inhibiting osteoblast differentiation. The variations in trabecular bone volume fraction and thickness (BV/TV and Tb.Th) were relatively higher with variations of one standard deviation in the levels of RANKL compared to OPG and Scl. This micro-MPA model will help us to better understand how cells respond to the mechanical signal by changing their activity in response to their local mechanical environment.