Benzophenone-3 drives osteoarthritis pathogenesis by regulating chondrocyte senescence

Benzophenone-3 (BP-3), a widely used UV absorber, is of increasing concern due to its potential health risks. Recent epidemiological studies have identified a link between BP-3 exposure and osteoarthritis (OA) prevalence, yet its specific role in OA pathogenesis remains incompletely understood. This study reveals that prolonged BP-3 exposure induces OA-like articular cartilage degeneration in rats, marked by structural disorganization, proteoglycan depletion, and critical dysregulation of extracellular matrix (ECM) homeostasis evidenced by up-regulated matrix metalloproteinases (MMPs) and down-regulated type II collagen (Col2a1). Notably, in human C28/I2 chondrocytes, BP-3 significantly disrupted ECM balance evidenced by increased MMPs and decreased Col2a1 content, which corroborates in vivo findings. Mechanistically, transcriptome analysis identified altered expression of genes associated with senescence in BP-3 exposure groups. Subsequent experiments confirmed that BP-3 induced chondrocyte senescence evidenced by elevated Senescence-Associated β-Galactosidase (SA-β-gal) activity and up-regulated p16, p21, and p53. Subsequent cellular transcriptomics further revealed significant changes in Mitogen-activated protein kinase (MAPK) signaling pathways following BP-3 exposure. Crucially, in chondrocytes, BP-3 exposure selectively activated ERK1/2 pathway but not p38 or JNK pathways within the MAPK cascade. Further investigation established that BP-3 drove p21 transcription via dual ERK-dependent mechanism: p53 phosphorylation at Ser15 and phosphorylation/nuclear translocation of the downstream ERK effector Ets-like transcription factor 1 (Elk-1). Strikingly, the ERK-specific inhibitor PD98059 effectively blocked BP-3-induced ERK activation, Elk-1 phosphorylation, chondrocyte senescence, and ECM degradation. Collectively, these findings establish a novel mechanism for BP-3 as an environmental osteoarthritic hazard, in which it triggers chondrocyte senescence and promotes OA pathogenesis through the specific activation of the ERK pathway.