PMID- 30835944 OWN - NLM STAT- MEDLINE DCOM- 20200130 LR - 20200130 IS - 2326-5205 (Electronic) IS - 2326-5191 (Linking) VI - 71 IP - 8 DP - 2019 Aug TI - Amelioration of Autoimmune Arthritis in Mice Treated With the DNA Methyltransferase Inhibitor 5'-Azacytidine. PG - 1265-1275 LID - 10.1002/art.40877 [doi] AB - OBJECTIVE: Disease-associated, differentially hypermethylated regions have been reported in rheumatoid arthritis (RA), but no DNA methyltransferase inhibitors have been evaluated in either RA or any animal models of RA. The present study was conducted to evaluate the therapeutic potential of 5'-azacytidine (5'-azaC), a DNA methyltransferase inhibitor, and explore the cellular and gene regulatory networks involved in the context of autoimmune arthritis. METHODS: A disease-associated genome-wide DNA methylation profile was explored by methylated CpG island recovery assay-chromatin immunoprecipitation (ChIP) in arthritic B cells. Mice with proteoglycan-induced arthritis (PGIA) were treated with 5'-azaC. The effect of 5'-azaC on the pathogenesis of PGIA was explored by measuring serum IgM and IgG1 antibody levels using enzyme-linked immunosorbent assay, investigating the efficiency of class-switch recombination (CSR) and Aicda gene expression using real-time quantitative polymerase chain reaction, monitoring germinal center (GC) formation by immunohistochemistry, and determining alterations in B cell subpopulations by flow cytometry. The 5'-azaC-induced regulation of the Aicda gene was explored using RNA interference, ChIP, and luciferase assays. RESULTS: We explored arthritis-associated hypermethylated regions in mouse B cells and demonstrated that DNA demethylation had a beneficial effect on autoimmune arthritis. The 5'-azaC-mediated demethylation of the epigenetically inactivated Ahr gene resulted in suppressed expression of the Aicda gene, reduced CSR, and compromised GC formation. Ultimately, this process led to diminished IgG1 antibody production and amelioration of autoimmune arthritis in mice. CONCLUSION: DNA hypermethylation plays a leading role in the pathogenesis of autoimmune arthritis and its targeted inhibition has therapeutic potential in arthritis management. CI - (c) 2019 University of Pecs. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. FAU - Toth, Daniel M AU - Toth DM AD - Rush University Medical Center, Chicago, Illinois. FAU - Ocsko, Timea AU - Ocsko T AD - Rush University Medical Center, Chicago, Illinois. FAU - Balog, Attila AU - Balog A AD - Albert Szent-Gyorgyi Clinical Center, Szeged, Hungary. FAU - Markovics, Adrienn AU - Markovics A AD - Rush University Medical Center, Chicago, Illinois. FAU - Mikecz, Katalin AU - Mikecz K AD - Rush University Medical Center, Chicago, Illinois. FAU - Kovacs, Laszlo AU - Kovacs L AD - Albert Szent-Gyorgyi Clinical Center, Szeged, Hungary. FAU - Jolly, Meenakshi AU - Jolly M AD - Rush University Medical Center, Chicago, Illinois. FAU - Bukiej, Aleksandra A AU - Bukiej AA AD - Rush University Medical Center, Chicago, Illinois. FAU - Ruthberg, Andrew D AU - Ruthberg AD AD - Rush University Medical Center, Chicago, Illinois. FAU - Vida, Andras AU - Vida A AD - Rush University Medical Center, Chicago, Illinois. FAU - Block, Joel A AU - Block JA AD - Rush University Medical Center, Chicago, Illinois. FAU - Glant, Tibor T AU - Glant TT AD - Rush University Medical Center, Chicago, Illinois. FAU - Rauch, Tibor A AU - Rauch TA AD - Rush University Medical Center, Chicago, Illinois, and University of Pecs, Pecs, Hungary. LA - eng SI - GENBANK/GSE98939 SI - GENBANK/GSE98932 GR - R01 AR059356/AR/NIAMS NIH HHS/United States GR - R01 AR062991/AR/NIAMS NIH HHS/United States GR - R21 AR064948/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190618 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (Enzyme Inhibitors) RN - M801H13NRU (Azacitidine) SB - IM MH - Animals MH - Arthritis, Experimental/*drug therapy/immunology MH - Arthritis, Rheumatoid/drug therapy/immunology MH - Autoimmune Diseases/drug therapy/immunology MH - Azacitidine/*pharmacology MH - B-Lymphocytes/immunology MH - Chromatin Immunoprecipitation MH - DNA Methylation/*drug effects MH - Disease Models, Animal MH - Enzyme Inhibitors/*pharmacology MH - Flow Cytometry MH - Gene Silencing MH - Mice EDAT- 2019/03/06 06:00 MHDA- 2020/01/31 06:00 CRDT- 2019/03/06 06:00 PHST- 2018/10/19 00:00 [received] PHST- 2019/02/28 00:00 [accepted] PHST- 2019/03/06 06:00 [pubmed] PHST- 2020/01/31 06:00 [medline] PHST- 2019/03/06 06:00 [entrez] AID - 10.1002/art.40877 [doi] PST - ppublish SO - Arthritis Rheumatol. 2019 Aug;71(8):1265-1275. doi: 10.1002/art.40877. Epub 2019 Jun 18.