Mechanical Overloading‐Induced Nanomineral Crystal Perturbation from the Osteochondral Interface: A Potential Initiator of Osteoarthritis

ABSTRACT As a common degenerative joint disease, osteoarthritis (OA) has been thoroughly studied for its pathogenesis, including cell phenotype and histological morphology changes. Yet, the nano‐micro scale spatiotemporal pathological progression, especially its original site and actuating events during OA progression remain largely unknown. Here, we first proposed that interface‐derived nanocrystal fragmentation and ectopic deposition subjected to mechanical overloading may be a potential initiator for OA progression. Ectopic deposition of nanocrystals results in mechanical stiffness of osteochondral interface extracellular matrix (ECM), which subsequently upregulates fibronectin and vitronectin expression from hypertrophic chondrocytes. Hyper‐mineralized vesicles, secreted by hypertrophic chondrocytes, facilitates the ECM bottom‐up mineralization and top‐down degeneration. Furthermore, mechanical overloading removal can block the ECM mineralization and degradation, and effectively reverse the OA pathology. The present work advances our comprehension of the underlying mechanisms of mechanical overloading induced OA progression and offers a foundation for potential OA therapeutic strategies.