2. Academic Validation
  3. Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis

Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis

  • Bone Res. 2025 Jun 11;13(1):60. doi: 10.1038/s41413-025-00437-w.
Kewei Rong # 1,  Dezheng Wang # 2,  Xiting Pu # 3 4,  Cheng Zhang 2,  Pu Zhang 1,  Xiankun Cao 1,  Jinglin Zheng 1,  Xiao Yang 1,  Kexin Liu 1,  Lei Shi 1,  Yin Li 1,  Peixiang Ma 1,  Dan Ye 2,  Jie Zhao 5,  Pu Wang 6,  An Qin 7
Affiliations

Affiliations

  • 1 Department of Orthopedics, Shanghai Key Laboratory of Orthopedics Implant, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
  • 3 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Shanghai Institute of Digestive Disease, Shanghai, China.
  • 5 Department of Orthopedics, Shanghai Key Laboratory of Orthopedics Implant, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. profzhaojie@126.com.
  • 6 Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China. wangpu@fudan.edu.cn.
  • 7 Department of Orthopedics, Shanghai Key Laboratory of Orthopedics Implant, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. dr_qinan@163.com.
  • # Contributed equally.
PMID: 40500265 DOI: 10.1038/s41413-025-00437-w
Abstract

Itaconate, a macrophage-specific anti-inflammatory metabolite, has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis. We found that itaconate is a TNF-α responsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts. In TNF-transgenic and Irg1-/- hybrid mice, a more severe bone destruction phenotype was observed. Administration of itaconate prevents excessive activation of osteoclasts by inhibiting TET2 enzyme activity. Furthermore, exogenous administration of itaconate or its derivative, 4-octyl-itaconate, inhibits arthritis progression and mitigates bone destruction, offering a potential therapeutic strategy for rheumatoid arthritis. This study elucidates that TNF-α drives macrophage-derived itaconate production to epigenetically suppress osteoclast hyperactivation through TET2 inhibition, establishing itaconate and its derivative OI as novel therapeutic agents against rheumatoid arthritis -associated bone destruction.

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