How bones learn to listen: In vivo models for investigating mechanosensitivity at bony interfaces in the ageing mouse

Beyond the well-documented loss of bone volume, the aged skeletal environment is marked by structural decay and the degenerated network of osteocytes, the bone cells responsible for orchestrating bone formation and resorption. Recent findings point towards the loss of mechanosensitivity and thus the 'deafened' adaptive response to mechanical loading as the driver of decreased bone formation. This imbalance results in a net loss of bone mass and, over time, increases skeletal fragility and fracture incidence. Although the responsiveness of bones to mechanical loading is typically diminished with age, newly formed bone during fracture healing remains responsive to mechanical stimulation. To date, the intrinsic quality of the newly formed bone tissue and the embedded osteocytes remain largely unknown. Given that invasive, longitudinal investigations are restricted in human subjects, mouse models serve as indispensable surrogates for researching changes in tissue mechanosensitivity within the context of ageing and regeneration. Combined with recent advances in quantitative histology-based approaches and time-lapsed three-dimensional high-resolution imaging, these models are well suited to address this knowledge gap and to investigate mechanosensitivity at the periosteal, endosteal, and intracortical interfaces. To this end, this work examines the key structural and cellular hallmarks of aged bone in mice, alongside the in vivo experimental models used to investigate the regenerative potential following fracture and the adaptive response to mechanical loading as vibration therapy. Finally, this review proposes that future therapeutic strategies should harness the regenerative process, together with targeted mechanical loading, to rejuvenate the degenerated osteocyte network. In doing so, bone may once again learn to 'listen' to mechanical vibrations and thereby help restore the functional quality of the ageing skeleton.