Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis
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<sup>-/-</sup> 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.
Authors
- Kewei Rong
- Dan Ye (ORCID: https://orcid.org/0000-0003-4848-0501)
- Xiao Yang (ORCID: https://orcid.org/0000-0001-5653-3234)
- Peixiang Ma (ORCID: https://orcid.org/0000-0001-6794-1663)
- Jie Zhao (ORCID: https://orcid.org/0000-0003-1000-5641)
- Dezheng Wang (ORCID: https://orcid.org/0000-0002-6449-1043)
- Xiting Pu
- An Qin (ORCID: https://orcid.org/0000-0002-8785-8848)
- Junke Zheng (ORCID: https://orcid.org/0000-0002-7023-2400)
- Xiankun Cao (ORCID: https://orcid.org/0000-0003-1993-8181)
- Pu Wang (ORCID: https://orcid.org/0000-0002-9185-1913)
- Pu Zhang (ORCID: https://orcid.org/0000-0003-4973-6716)
- Lei Shi (ORCID: https://orcid.org/0000-0002-9831-1872)
- Kexin Liu (ORCID: https://orcid.org/0000-0002-1379-4247)
- Cheng Zhang (ORCID: https://orcid.org/0000-0002-9218-5019)
- Yin Li (ORCID: https://orcid.org/0000-0002-0944-9897)
Institutions
- Shanghai Medical College of Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- Shanghai Ninth People's Hospital (CN)
- State Key Laboratory of Oncogene and Related Genes (CN)
- Ministry of Science and Technology (LA)
- Shanghai Institute of Hematology (CN)
- Huashan Hospital (CN)
Publication Details
- Journal
- Bone Research
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1038/s41413-025-00437-w
- Citations
- 9
- Primary Topic
- Bone and Joint Diseases
- Type
- article
- Field-Weighted Citation Impact
- 15.49
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Jiao Tong University
- School of Medicine, Shanghai Jiao Tong University
- National Natural Science Foundation of China-Yunnan Joint Fund