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, we established <i>in vitro</i> and <i>in vivo</i> models of prolonged moderate mechanical loading (7.5% strain, 1 Hz) and analyzed human cartilage from weight-bearing and non-weight-bearing regions using RNA sequencing. Prolonged exposure (≥ 12 h) significantly increased chondrocyte apoptosis (2.3-fold), reduced expression of the chondrogenic transcription factor SOX9 and the matrix markers 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 mechanically 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 patients with early OA may benefit from limiting high-impact or prolonged moderate-intensity exercise sessions to prevent cartilage damage and guide rehabilitation.