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In this Perspective, we discuss the current evidence on the smokingOA association and examine how both conventional cigarette smoke and EC aerosol may contribute to OA through six interrelated immune-inflammatory pathways: exposure-specific effects, synovial macrophage activation, DAMP-mediated nuclear factor kappa-B (NF-B) signaling, inflammasome activation, T helper cell 17 (Th17)/regulatory T cell (Treg) imbalance, and microRNA (miRNA) dysregulation