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OBJECTIVES: Genome-wide association studies have connected PADI4, encoding peptidylarginine deiminase 4 (PAD4), with rheumatoid arthritis (RA). PAD4 promotes neutrophil extracellular trap (NET) formation. We studied Padi4 origin and NETs in an arthritis model in C57BL/6 mice. METHODS: To permit the effective use of C57BL/6 mice in the collagen-induced arthritis (CIA) model, we introduced the administration of granulocyte colony-stimulating factor (G-CSF) for four consecutive days in conjunction with the booster immunization on day 21. The model evaluated global (Padi4(−/−)) and hematopoietic lineage-specific (Padi4(Vav1Cre/+)) Padi4-deficient mice. RESULTS: G-CSF significantly increased the incidence and severity of arthritis in CIA. G-CSF-treated mice showed elevated citrullinated histone H3 (H3Cit) in plasma while vehicle-treated mice did not. Immunofluorescent microscopy revealed deposition of H3Cit in synovial tissue in G-CSF-treated mice. Padi4(−/−) mice developed less arthritis, demonstrating lower serum interleukin 6 and plasma H3Cit, less citrullinated histone H4 in synovial tissue, and less bone erosion observed by micro-computed tomography than Padi4(+/+) mice in the G-CSF-modified CIA model. Similarly, Padi4(Vav1Cre/+) mice developed less arthritis compared with Padi4(fl/fl) mice, and presented the same phenotype as Padi4(−/−) mice. CONCLUSIONS: We succeeded in developing an arthritis model suitable for use in C57BL/6 mice that was fully compliant with high animal welfare standards. We observed an over 90% incidence of arthritis in male mice and detectable NET markers. This model, with some futures consistent with human RA, demonstrates that hematopoietic PAD4 is an important contributor to arthritis development and may prove useful in future RA research. |
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