1. Academic Validation
  2. Reversal of Epigenetic Peroxisome Proliferator-Activated Receptor-γ Suppression by Diacerein Alleviates Oxidative Stress and Osteoarthritis in Mice

Reversal of Epigenetic Peroxisome Proliferator-Activated Receptor-γ Suppression by Diacerein Alleviates Oxidative Stress and Osteoarthritis in Mice

  • Antioxid Redox Signal. 2022 Jul;37(1-3):40-53. doi: 10.1089/ars.2021.0219.
Xingren Chen 1 Xiaobo Zhu 1 Jian Dong 1 Fang Chen 2 Qi Gao 2 Lijun Zhang 2 Dawei Cai 1 Hui Dong 3 Binjia Ruan 3 Yongxiang Wang 3 Qing Jiang 1 Wangsen Cao 2
Affiliations

Affiliations

  • 1 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.
  • 2 Nanjing University School of Medicine, Department of Basic Medical Science, Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China.
  • 3 Department of Orthopedics, Northern Jiangsu People's Hospital, The Affiliated Hospital of Nanjing University Medical School, Yangzhou, China.
Abstract

Aims: 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. Results: 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. Innovation: 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. Conclusion: DNA methylation aberration and the resultant PPARγ suppression contribute significantly to epigenetic OA pathogenesis, and targeting PPARγ suppression via DNA demethylation is an important component of diacerein's anti-OA functions. Antioxid. Redox Signal. 37, 40-53.

Keywords

DNA methylation; PPARγ; diacerein; epigenetics; osteoarthritis; oxidative stress.

Figures
Products