Dysregulated mechanoregulation of load-induced bone adaptation in prematurely aged mice: insights from a micro-multiphysics agent-based model

Abstract Bone exhibits remarkable ability to adapt to varying mechanical demands. Aging can lead to changes in distribution of cells and proteins that directly affect bone formation and resorption. Given the inherent challenges of quantifying these cellular and protein alterations in vivo , innovative in silico tools have proven useful to contribute to studying the impact of aging on bone mechanobiology and associated cellular mechanisms. Here, we employed an agent-based in silico analysis of in vivo micro-computed tomography data of prematurely aged mice to examine the effects of aging and mechanical loading on bone cells and their mechanome, the intrinsic cellular system sensing mechanical forces. Our results from applying a micro-multiphysics agent-based model to an in vivo model of premature aging (PolG) showed that aging disrupts mechanoregulation of load-induced bone formation and resorption by eliminating the increase in bone formation through diminished osteoblast activity and mineralization, alongside mechanomic alterations. Specifically, prematurely aged mice exhibited a higher frequency of quiescence at higher mechanical signals and the simulations showed that the number of lining cells and osteoclasts per bone surface increased with age. Normalized trabecular thickness was more positively associated with the ratio of osteoblast to osteoclast number (Ob.N/Oc.N) in the aged control and aged loading groups (R 2 =0.58 and 0.61), than in young control and loading groups (R 2 =0.06 and 0.27), indicating dysregulated remodeling dynamics during aging. In conclusion, our results show that in silico tools can give valuable insights into the changes in mechanoregulation and cellular mechanisms occurring under physiological and aging conditions.