Targeting hexokinase 2 alleviates synovial pathology and protects cartilage in osteoarthritis

Osteoarthritis (OA) is a common joint disorder marked by progressive cartilage loss accompanied by persistent synovial inflammation. The metabolic mechanisms driving synovial pathology in OA are not fully understood. Hexokinase 2 (HK2), a key glycolytic enzyme, was investigated as a potential mediator in this process. HK2 expression was analyzed in OA synovial tissues. In vitro, HK2 was knocked down in fibroblast-like synoviocytes (FLSs). Measurements included expression of pro-inflammatory cytokines (IL-1β, TNF-α), senescence markers (p16INK4a, p21, p53), reactive oxygen species (ROS), mitochondrial function, glycolytic activity, and oxidative stress. The impact of HK2-silenced FLSs on co-cultured chondrocytes was assessed by evaluating cartilage matrix protein expression and catabolic enzyme levels. HK2 was significantly upregulated in OA synovial tissues, along with increased inflammatory cytokines, senescence markers, and ROS. HK2 knockdown in FLSs restored mitochondrial function, reduced glycolysis and oxidative stress, and downregulated senescence-associated proteins. These FLSs also produced fewer inflammatory cytokines and, in co-culture, protected chondrocytes by enhancing cartilage matrix protein expression and reducing catabolic enzyme levels. HK2 promotes synovial inflammation, cellular senescence, and chondrocyte dysfunction in OA through metabolic reprogramming. Targeting HK2 may represent a promising therapeutic strategy for OA.