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Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages

Nature volume 443, pages 9981002 (26 October 2006) | Download Citation

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  • An Erratum to this article was published on 01 March 2007

Abstract

A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis1. DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them1,2. Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-α was upregulated in the bone marrow, and administration of anti-TNF-α antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-α, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.

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Acknowledgements

We thank K. Aozasa for pathological analysis of the mice, P. Quartier for critical reading of our manuscript, M. Nishikawa, H. Matsuda, T. Matsuki, A. Seiyama and T. Yanagida for advice and discussion, H. Fukuyama for help at the initial stage of this work, and M. Fujii and M. Harayama for secretarial assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture in Japan.

Author information

Author notes

    • Keiko Miwa

    Present address: Laboratory of Cell Lineage Modulation, RIKEN Kobe Institute, Kobe 650-0047, Japan.

Affiliations

  1. Department of Genetics and,

    • Kohki Kawane
    • , Mayumi Ohtani
    • , Keiko Miwa
    •  & Shigekazu Nagata
  2. Department of Orthopaedics, Osaka University Medical School, Osaka 565-0871, Japan

    • Takuji Kizawa
    •  & Hideki Yoshikawa
  3. Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan

    • Kohki Kawane
    •  & Shigekazu Nagata
  4. Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan

    • Kohki Kawane
    • , Mayumi Ohtani
    • , Keiko Miwa
    •  & Shigekazu Nagata
  5. High Field Magnetic Resonance Imaging Research Institute, Advanced Medical Science Research Centre, Iwate Medical University, Takizawa 020-0173, Japan

    • Yoshiyuki Kanbara
    •  & Yoshichika Yoshioka

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Shigekazu Nagata.

Supplementary information

Word documents

  1. 1.

    Supplementary Methods

    Materials and methods are described in detail.

  2. 2.

    Supplementary Figure Legends

    This file contains text describing Supplementary Figures 1, 2, and 3

Image files

  1. 1.

    Supplementary Figure 1

    Targeting vector for the inducible deletion of the DNase II gene.

  2. 2.

    Supplementary Figure 2

    Inducible deletion of the DNase II gene.

  3. 3.

    Supplementary Figure 3

    No expression of DNase II mRNA in poly(I:C)-treated mice.

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DOI

https://doi.org/10.1038/nature05245

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