Long-term mechanical loading aggravates osteoarthritis through a pro-apoptotic inflammatory microenvironment

Articular cartilage maintains joint homeostasis by adapting to mechanical loading, but both insufficient and excessive loading can impair cartilage integrity. Whether mechanical activity should be restricted in early osteoarthritis (OA), particularly among exercise enthusiasts, remains controversial. Here, in vitro and in vivo models of prolonged moderate mechanical loading (7.5% strain, 1 Hz) were established, and human cartilage from weight-bearing and non-weight-bearing regions was analyzed by RNA sequencing. Prolonged exposure（≥12 h）significantly increased chondrocyte apoptosis (2.3-fold), reduced matrix markers SOX9 and COL2A1, and elevated nerve growth factor (NGF) expression (1.8-fold), accompanied by enrichment of neural sensitization and inflammatory pathways. Immunofluorescence staining revealed NGF accumulation in load-stressed cartilage. Unlike high-intensity stress, which led to immediate apoptosis, moderate loading induced a delayed pro-apoptotic response after 12 h. These findings indicate that prolonged moderate mechanical loading may promote chondrocyte apoptosis through an NGF-mediated inflammatory microenvironment and provide mechanistic evidence suggesting that early OA patients may benefit from limiting high-impact exercise sessions to prevent cartilage damage and to guide rehabilitation.