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Epigenetic regulator UHRF1 orchestrates proinflammatory gene expression in rheumatoid arthritis in a suppressive manner
Noritaka Saeki, … , Shu Takeda, Yuuki Imai
Noritaka Saeki, … , Shu Takeda, Yuuki Imai
Published April 26, 2022
Citation Information: J Clin Invest. 2022;132(11):e150533. https://doi.org/10.1172/JCI150533.
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Research Article Autoimmunity Bone biology Article has an altmetric score of 19

Epigenetic regulator UHRF1 orchestrates proinflammatory gene expression in rheumatoid arthritis in a suppressive manner

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Abstract

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, the epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here, we showed that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is a central epigenetic regulator that orchestrates multiple pathogeneses in RA in a suppressive manner. UHRF1 expression was remarkably upregulated in synovial fibroblasts (SFs) from arthritis model mice and patients with RA. Mice with SF-specific Uhrf1 conditional knockout showed more severe arthritic phenotypes than littermate controls. Uhrf1-deficient SFs also exhibited enhanced apoptosis resistance and upregulated expression of several cytokines, including Ccl20. In patients with RA, DAS28, CRP, and Th17 accumulation and apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, Ryuvidine administration stabilized UHRF1 ameliorated arthritis pathogeneses in a mouse model of RA. This study demonstrated that UHRF1 expressed in RA SFs can contribute to negative feedback mechanisms that suppress multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be one of the therapeutic strategies for RA.

Authors

Noritaka Saeki, Kazuki Inoue, Maky Ideta-Otsuka, Kunihiko Watamori, Shinichi Mizuki, Katsuto Takenaka, Katsuhide Igarashi, Hiromasa Miura, Shu Takeda, Yuuki Imai

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Figure 8

Uhrf1 stabilization attenuates arthritis pathogenesis.

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Uhrf1 stabilization attenuates arthritis pathogenesis.
(A) Western blot ...
(A) Western blot analysis of UHRF1 expression in HEK293 cells. Cell cycle was synchronized with aphidicolin (G1/S phase) or nocodazole (G2/M phase) before cells were treated with UNC0379 (U), NSC663284 (N), BVT948 (B), or Ryuvidine (R). (B) Protocol to assess efficacy of Ryuvidine in STA. (C) Immunofluorescence staining for Uhrf1 (red), Pdpn (green), and DAPI (blue) in WT STA with or without Ryuvidine treatment. Scale bar: 50 μm. Quantification of Uhrf1+ Pdpn+ (arrow) per population of Pdpn+ cells. Development of (D) hind paw thickness and (E) clinical score in WT and Uhrf1ΔCol6a1 mice with or without Ryuvidine injection after STA induction. (F) Development of clinical score in DBA/1 mice with or without Ryuvidine injection after collagen-induced arthritis induction. (G) Representative safranin O, fast green, and eosin staining in WT STA. Scale bar: 200 μm. Quantification of synovium thickness in WT STA after Ryuvidine treatment. (H) Immunofluorescence staining for Cl-Casp3 (red), Pdpn (green), and DAPI (blue) in WT STA with or without Ryuvidine treatment. Scale bar: 50 μm. Quantification of Cl-Casp3+ Pdpn+ (arrow) per population of Pdpn+ cells. (I) Quantification of Ccl20 serum levels in WT STA after Ryuvidine treatment. (J) H&E staining and immunofluorescence staining for UHRF1 (red); PDPN, TUNEL (green); and DAPI (blue) in RASF organoids with or without Ryuvidine treatment. Scale bar: 50 μm. Quantification of cell number in lining layer, UHRF1+ among DAPI+ (arrow) cells in the lining layer and TUNEL+ cells per DAPI+ (arrowhead) cells in the field. WT + DMSO; n = 8–12, WT + Ryuvidine; n = 10–12, Uhrf1ΔCol6a1 + DMSO; n = 5, Uhrf1ΔCol6a1 + Ryuvidine; n = 5, DBA/1 + DMSO; n = 8, DBA/1 + Ryuvidine; n = 7, organoid culture; n = 8. Mean ± SD. *P < 0.05 and **P < 0.01 versus DMSO by unpaired t test in C–I, and ANOVA followed by Tukey’s test in J. Data in A were technically replicated. Data in B–J obtained from 5–12 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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