Leptin showed different apoptosis regulation effects on the chondrocytes from tibial and vertebral epiphyseal plates. However, the mechanism is still unclear. In this study, we tested the protein profile of tibial and vertebral epiphyseal plate chondrocytes with and without leptin stimulation by mass spectrometry and found that the histone acetylation level of tibial chondrocytes was decreased after leptin treatment, while increased in vertebral epiphyseal plates. COIP assay showed that leptin promoted H3, H4 histone acetylation by recruiting CREB binding protein (CBP)/P300 to activate histone acetyl transferases (HATs) activity in vertebral disc chondrocytes. But in tibial plate cartilage cells, leptin did not recruit CBP and p300, thus differently affect the apoptosis of epiphyseal plate chondrocytes. Through explored the mechanism of histone acetylation modulated by leptin, and its effect on cartilage cell apoptosis and cell cycle regulation, This provides a novel target therapy possibility therapeutic approach to for the related disease.