Methyl-CpG-binding domain 2 mitigates osteoarthritis through Steap3 promoter methylation and chondrocyte ferroptosis regulation

作者：Renpeng Peng, Meng Zheng, Honglei Kang, Yimin Dong, Pengju Wang, Cong‐Yi Wang, Jun Xiao, Feng Li, Xuying Sun · 发表于：Experimental & Molecular Medicine · 年份：2025 · DOI：10.1038/s12276-025-01586-y · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Osteoarthritis Treatment and Mechanisms

Abstract Extensive research has underscored the pivotal role of DNA methylation in the development of various diseases, including osteoarthritis (OA). DNA methylation is regulated by methylation writers, readers, and erasers. As a crucial methylation reader, methyl-CpG-binding domain2 (MBD2) has been implicated in modulating the occurrence and progression of multiple inflammatory diseases. This study aims to investigate whether MBD2 contributes to the pathogenesis of OA through its regulation of DNA methylation. Our study confirmed that MBD2 was increased in OA cartilage tissues from humans as well as mice with destabilization of the medial meniscus, despite a reduction in its nuclear import. Specific knockout of Mbd2 in cartilage exacerbated cartilage degradation and accelerated OA progression. Mechanistically, RNA sequencing studies demonstrated that the deletion of MBD2 induced ferroptosis in chondrocytes. Subsequent CUT&Tag and reduced representation bisulfite sequencing analyses revealed that MBD2 binds to the Steap3 promoter region and modulates its methylation state in chondrocytes. STEAP3 catalyzes the reduction of ferric iron (Fe 3+ ) to ferrous iron (Fe 2+ ), contributing to the induction of ferroptosis. The administration of a ferroptosis inhibitor and adeno-associated virus-mediated Steap3 knockdown alleviated OA induced by MBD2 deletion. Adeno-associated virus-mediated overexpression of Mbd2 partially mitigated destabilization of the medial meniscus-induced O...