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Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation

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An Author Correction to this article was published on 15 March 2024

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Abstract

Osteoporosis is a chronic disease that endangers the health of the elderly. Inhibiting osteoclast hyperactivity is a key aspect of osteoporosis prevention and treatment. Several studies have shown that interferon regulatory factor 9 (IRF9) not only regulates innate and adaptive immune responses but also plays an important role in inflammation, antiviral response, and cell development. However, the exact role of IRF9 in osteoclasts has not been reported. To elucidate the role of IRF9 in osteoclast differentiation, we established the ovariectomized mouse model of postmenopausal osteoporosis and found that IRF9 expression was reduced in ovariectomized mice with overactive osteoclasts. Furthermore, knockdown of IRF9 expression enhanced osteoclast differentiation in vitro. Using RNA sequencing, we identified that the differentially expressed genes enriched by IRF9 knockdown were related to ferroptosis. We observed that IRF9 knockdown promoted osteoclast differentiation via decreased ferroptosis in vitro and further verified that IRF9 knockdown reduced ferroptosis by activating signal transducer and activator of transcription 3 (STAT3) to promote osteoclastogenesis. In conclusion, we identified an essential role of IRF9 in the regulation of osteoclastogenesis in osteoporosis and its underlying mechanism.

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Acknowledgements

We thank Prof. Zhaowei Xu of Fujian Medical University for valuable discussion.

Funding

This work was supported by the grants from the Startup Fund for Scientific Research, Fujian Medical University (No. 2021QH2033), the Natural Science Foundation of Fujian Province (No. 2020J02052), and the Scientific and Technological Major Special Project of Fujian Provincial Health Commission (No. 2021ZD01004).

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Chao Lan, Xuan Zhou, Ximei Shen, Youfen Lin, Xiaoyuan Chen, Jiebin Lin, Yongze Zhang & Sunjie Yan

  2. Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China

    Chao Lan, Xuan Zhou, Ximei Shen, Youfen Lin, Yongze Zhang & Sunjie Yan

  3. Clinical Research Center for Metabolic Diseases of Fujian Province, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Chao Lan, Xuan Zhou, Ximei Shen, Youfen Lin, Yongze Zhang & Sunjie Yan

  4. Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Chao Lan, Xuan Zhou, Ximei Shen, Youfen Lin, Yongze Zhang & Sunjie Yan

  5. Diabetes Research Institute of Fujian Province, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Chao Lan, Xuan Zhou, Ximei Shen, Youfen Lin, Yongze Zhang & Sunjie Yan

  6. Metabolic Diseases Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Chao Lan, Xuan Zhou, Ximei Shen, Youfen Lin, Yongze Zhang & Sunjie Yan

  7. Orthopedics Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China

    Lifeng Zheng

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  1. Chao Lan
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Contributions

Sunjie Yan and Ximei Shen designed the research. Chao Lan, Youfen Lin, and Ximei Shen wrote the paper. Chao Lan, Xuan Zhou, Xiaoyuan Chen, Jiebin Lin, Yongze Zhang, and Lifeng Zheng performed the experiments and analyzed the data.

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Correspondence to Sunjie Yan.

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Chao Lan, Xuan Zhou, and Ximei Shen contributed equally to this work

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Lan, C., Zhou, X., Shen, X. et al. Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation. Inflammation 47, 99–113 (2024). https://doi.org/10.1007/s10753-023-01896-1

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