In Situ Profiling of Nanoscale Strains Uncovers Mechano‐Architectural Predictors of Aging and Osteoarthritis Emergence

ABSTRACT Coordinated load transfer across knee joint compartments underpins lifelong joint function, yet dysregulated mechanics are also widely implicated in the etiology of osteoarthritis (OA). How physiological loads are accommodated in the healthy joint and how regionalized architectural alterations reconfigure joint‐level mechanics to promote OA, however, remain unresolved. Here, we integrate in situ mechanical loading of murine tibial epiphyses with phase‐contrast synchrotron X‐ray computed tomography and digital volume correlation to quantify three‐dimensional, compartment‐specific load‐bearing behavior in intact healthy (CBA) and OA‐prone (STR/Ort) knee joints. We find that raised focal strain concentrations emerge within the subchondral plate and precede histological cartilage degeneration in STR/Ort joints at 10 weeks of age. In contrast, these strain concentrations are absent in both young and aging CBA mice, where mechanical strain is preferentially transmitted to locations distant from the articular surface. Finite element modeling further reveals that strain localization in STR/Ort joints is governed by region‐specific microstructural incongruities. Together, these findings demonstrate that epiphyseal microarchitecture preserves mechanical homeostasis during healthy aging, whereas spatial disorganization of subchondral microarchitecture renders the epiphysis susceptible to load‐induced failure. Collectively, this work identifies mechano‐architectural misalignment within the mineralized phase of the tibial epiphysis as an early mechanical promoter of OA emergence.