Basic calcium phosphate crystals aggravate senescence-related osteoarthritis through GPX4-NRF2-mediated ferroptosis

Osteoarthritis (OA) is a degenerative joint disorder strongly associated with senescence, involving pathological processes such as reactive oxygen species (ROS) accumulation and ferroptosis. Basic calcium phosphate (BCP) crystals are frequently found in the joints of OA patients, yet their role in OA pathogenesis remains poorly understood. Here, we aimed to investigate the role of synthetic BCP crystals in promoting OA progression and to elucidate the molecular mechanisms underlying senescence. In this study, a rat OA model was established by intra-articular injections of BCP crystals into the knee joint, and the effect of BCP crystals improving the ferroptosis phenotype of OA cartilage was investigated. Furthermore, the expression of senescence-related biomarkers and mitochondrial functions in BCP-treated chondrocytes was observed. Moreover, the role of synthetic BCP crystals in promoting ferroptosis process in chondrocytes was investigated, as well as their mechanism of action in OA, which was related to chondrocyte senescence. The in vivo findings demonstrated that BCP crystals accelerated cartilage senescence, worsened cartilage degradation, promoted osteophyte formation, and induced ferroptosis in the joint synovium. In vitro, BCP crystals intensified ferroptosis and oxidative stress in rat chondrocytes, increased ROS production, and further promoted mitochondrial dysfunction and chondrocyte senescence. Mechanistically, BCP crystals aggravated senescence-related pathological changes by inhibiting of the GPX4-NRF2 pathway and inducing ferroptosis, thereby promoting OA progression. Our findings demonstrate BCP crystals promote chondrocyte senescence by enhancing mitochondrial dysfunction and ferroptosis. This effect was mediated through downregulation of GPX4-NRF2 signaling, which provided a theoretical basis for exploring the pathogenesis and treatment of OA.