1. Department of Genetics and,
2. Department of Orthopaedics, Osaka University Medical School, Osaka 565-0871, Japan
3. Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
4. Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan
5. High Field Magnetic Resonance Imaging Research Institute, Advanced Medical Science Research Centre, Iwate Medical University, Takizawa 020-0173, Japan
6. Present address: Laboratory of Cell Lineage Modulation, RIKEN Kobe Institute, Kobe 650-0047, Japan.

Correspondence to: Shigekazu Nagata^1,3,4 Correspondence and requests for materials should be addressed to S.N. (Email: nagata@genetic.med.osaka-u.ac.jp).

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 them^{1, 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)- was upregulated in the bone marrow, and administration of anti-TNF- 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-, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.

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