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

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.

• Authors: Xingren Chen, Xiaobo Zhu, Jian Dong, Fang Chen, Qi Gao, Lijun Zhang, Dawei Cai, Hui Dong, Binjia Ruan, Yongxiang Wang, Qing Jiang, Wangsen Cao
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 37 Issue 1-3 Pg. 40-53 (07 2022) ISSN: 1557-7716 [Electronic] United States
• PMID: 35196878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthraquinones
• Antioxidants
• PPAR gamma
• diacerein

Topics

• Animals
• Anthraquinones (pharmacology, therapeutic use)
• Antioxidants (metabolism)
• Epigenesis, Genetic
• Mice
• Mice, Knockout
• Osteoarthritis (drug therapy, genetics, metabolism)
• Oxidative Stress
• PPAR gamma (metabolism)