Age- and Sex-Specific Deterioration on Bone and Osteocyte Lacuno-Canalicular Network in a Mouse Model of Premature Aging

Age-related osteoporosis poses a significant challenge in musculoskeletal health; a condition characterized by reduced bone density and increased fracture susceptibility in older individuals necessitates a better understanding of underlying molecular and cellular mechanisms. Emerging evidence suggests that osteocytes are the pivotal orchestrators of bone remodeling and represent novel therapeutic targets for age-related bone loss. Our study uses the prematurely aged PolgD257A/D257A (PolgA) mouse model to scrutinize age- and sex-related alterations in musculoskeletal health parameters (frailty, grip strength, gait data), bone and particularly the osteocyte lacuno-canalicular network (LCN). Moreover, we introduced a novel staining method for undecalcified fresh frozen bone sections along with a new quantitative in silico image analysis pipeline to evaluate the alterations in the osteocyte network with aging. Our findings underscore the pronounced degenerative changes in the musculoskeletal health parameters, bone and osteocyte LCN in PolgA mice as early as 40 weeks with more prominent alterations evident in aged males. Our findings suggest that the PolgA mouse model serves as a valuable model for studying the cellular mechanisms underlying age-related bone loss, given the comparable aging signs and age-related degeneration of the bone and the osteocyte network observed in naturally aging mice and elderly humans.