In this study, we showed that nicotine at a dose under the actual exposure of nicotine dependence in daily life had an adverse effect on the chondrogenic repair of BMSCs in cartilage defects and that nicotine suppressed BMSC chondrogenic differentiation via the activation Ca2+/Calcineurin/NFATc2 signaling, which decreased the histone acetylation of the Sox9 promoter region. Here, SOX9 is linked to nicotine dependence.