Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedics, State Key Lab of Pharmaceutical Biotechnology, Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University School of Medicine, Nanjing, China.
Nanjing University School of Medicine, Department of Basic Medical Science, Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China.
Antioxid Redox Signal. 2022 Jul;37(1-3):40-53. doi: 10.1089/ars.2021.0219.
The pathogenesis of osteoarthritis (OA) is characterized by oxidative stress (OS) and sustained inflammation that are substantially associated with epigenetic DNA methylation alterations of osteogenic gene expression. Diacerein as an anthraquinone anti-OA drug exhibits multiple chondroprotective properties, but less clarified pharmacological actions. Since anthraquinone contain an epigenetic modulating property, in this study we investigate whether the anti-OA functions of diacerein involve DNA methylation modulation and antioxidant signaling. The OA mice incurred by destabilization of medial meniscus exhibited marked suppression of peroxisome proliferator-activated receptor-gamma (PPARγ), a chondroprotective transcription factor with anti-inflammation and OS-balancing properties, aberrant upregulations of DNA methyltransferase (DNMT)1/3a, and PPARγ promoter hypermethylation in knee joint cartilage. Diacerein treatment mitigated the cartilage damage and significantly inhibited the DNMT1/3a upregulation, the PPARγ promoter hypermethylation, and the PPARγ loss, and it effectively corrected the adverse expression of antioxidant enzymes and inflammatory cytokines. In cultured chondrocytes, diacerein reduced the interleukin-1β-induced PPARγ suppression and the abnormal expression of its downstream antioxidant enzymes in a gain of DNMT and PPARγ inhibition-sensitive manner, and in PPARγ knockout mice, the anti-OA effects of diacerein were significantly reduced. Our work reveals a novel anti-OA pharmacological property of diacerein and identifies the aberrant DNMT elevation and the resultant PPARγ suppression as an important epigenetic pathway that mediates diacerein's anti-OA activities. DNA methylation aberration and the resultant PPARγ suppression contribute significantly to epigenetic OA pathogenesis, and targeting PPARγ suppression DNA demethylation is an important component of diacerein's anti-OA functions. 37, 40-53.
骨关节炎（OA）的发病机制以氧化应激（OS）和持续炎症为特征，这些特征与成骨基因表达的表观遗传 DNA 甲基化改变密切相关。二乙酰氨己酸作为蒽醌类抗 OA 药物具有多种软骨保护特性，但药理作用不太明确。由于蒽醌类化合物具有表观遗传调节特性，因此本研究旨在探讨二乙酰氨己酸的抗 OA 作用是否涉及 DNA 甲基化调节和抗氧化信号。由内侧半月板不稳定引起的 OA 小鼠表现出过氧化物酶体增殖物激活受体-γ（PPARγ）明显抑制，PPARγ是一种具有抗炎和 OS 平衡特性的软骨保护转录因子，其下游的 DNA 甲基转移酶（DNMT）1/3a 和 PPARγ 启动子过度甲基化在膝关节软骨中。二乙酰氨己酸治疗减轻了软骨损伤，并显著抑制了 DNMT1/3a 的上调、PPARγ 启动子过度甲基化和 PPARγ 的丢失，并且有效纠正了抗氧化酶和炎症细胞因子的不良表达。在培养的软骨细胞中，二乙酰氨己酸以增加 DNMT 和 PPARγ 抑制敏感的方式降低了白细胞介素-1β诱导的 PPARγ 抑制和其下游抗氧化酶的异常表达，在 PPARγ 敲除小鼠中，二乙酰氨己酸的抗 OA 作用明显降低。我们的工作揭示了二乙酰氨己酸的一种新的抗 OA 药理特性，并确定异常的 DNMT 升高和由此导致的 PPARγ 抑制是介导二乙酰氨己酸抗 OA 活性的重要表观遗传途径。DNA 甲基化异常和由此导致的 PPARγ 抑制对表观遗传 OA 的发病机制有重要贡献，靶向 PPARγ 抑制 DNA 去甲基化是二乙酰氨己酸抗 OA 作用的重要组成部分。37、40-53。
