{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:17:08Z","timestamp":1791476228797,"version":"4.3.4"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflamm Regener"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by tumor-like hyperplasia and inflammation of the synovium, which causes synovial cell invasion into the bone and cartilage. In RA pathogenesis, various molecules in effector cells (i.e., immune cells and mesenchymal cells) are dysregulated by genetic and environmental factors. Synovial fibroblasts (SFs), the most abundant resident mesenchymal cells in the synovium, are the major local effectors of the destructive joint inflammation and exert their effects through the pathogenic production of molecules such as interleukin-6.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Main body<\/jats:title>\n                <jats:p>To date, more than 100 RA susceptibility loci have been identified in genome-wide association studies (GWASs), and finding novel therapeutic targets utilizing genome analysis is considered a promising approach because some candidate causal genes identified by GWASs have previously been established as therapeutic targets. For further exploration of RA-responsible cells and cell type-specific therapeutic targets, integrated analysis (or functional genome analysis) of the genome and intermediate traits (e.g., transcriptome and epigenome) is crucial.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This review builds on the existing knowledge regarding the epigenomic abnormalities in RASFs and discusses the recent advances in single-cell analysis, highlighting the prospects of SFs as targets for safer and more effective therapies against RA.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s41232-021-00157-8","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:02:53Z","timestamp":1614556973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Multiomics landscape of synovial fibroblasts in rheumatoid arthritis"],"prefix":"10.1186","volume":"41","author":[{"given":"Haruka","family":"Tsuchiya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mineto","family":"Ota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7276-5254","authenticated-orcid":false,"given":"Keishi","family":"Fujio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,1]]},"reference":[{"issue":"7488","key":"157_CR1","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature12873","volume":"506","author":"Y Okada","year":"2014","unstructured":"Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376\u201381. https:\/\/doi.org\/10.1038\/nature12873.","journal-title":"Nature."},{"issue":"7539","key":"157_CR2","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature13835","volume":"518","author":"KK Farh","year":"2015","unstructured":"Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337\u201343. https:\/\/doi.org\/10.1038\/nature13835.","journal-title":"Nature."},{"key":"157_CR3","doi-asserted-by":"publisher","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","volume":"4","author":"JS Smolen","year":"2018","unstructured":"Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid Arthritis. Nat Rev Dis Primers. 2018;4:18001. https:\/\/doi.org\/10.1038\/nrdp.2018.1.","journal-title":"Nat Rev Dis Primers."},{"issue":"7","key":"157_CR4","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/s41590-019-0378-1","volume":"20","author":"F Zhang","year":"2019","unstructured":"Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928\u201342. https:\/\/doi.org\/10.1038\/s41590-019-0378-1.","journal-title":"Nat Immunol."},{"issue":"1","key":"157_CR5","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1136\/annrheumdis-2012-201526","volume":"72","author":"K Nakano","year":"2013","unstructured":"Nakano K, Whitaker JW, Boyle DL, Wang W, Firestein GS. DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis. 2013;72(1):110\u20137. https:\/\/doi.org\/10.1136\/annrheumdis-2012-201526.","journal-title":"Ann Rheum Dis."},{"key":"157_CR6","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.jaut.2012.12.005","volume":"41","author":"L de la Rica","year":"2013","unstructured":"de la Rica L, Urquiza JM, Gomez-Cabrero D, Islam AB, Lopez-Bigas N, Tegner J, et al. Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J Autoimmun. 2013;41:6\u201316. https:\/\/doi.org\/10.1016\/j.jaut.2012.12.005.","journal-title":"J Autoimmun."},{"issue":"4","key":"157_CR7","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/gm444","volume":"5","author":"JW Whitaker","year":"2013","unstructured":"Whitaker JW, Shoemaker R, Boyle DL, Hillman J, Anderson D, Wang W, et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 2013;5(4):40. https:\/\/doi.org\/10.1186\/gm444.","journal-title":"Genome Med."},{"issue":"7","key":"157_CR8","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1002\/art.39123","volume":"67","author":"R Ai","year":"2015","unstructured":"Ai R, Whitaker JW, Boyle DL, Tak PP, Gerlag DM, Wang W, et al. DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 2015;67(7):1978\u201380. https:\/\/doi.org\/10.1002\/art.39123.","journal-title":"Arthritis Rheumatol."},{"issue":"1","key":"157_CR9","doi-asserted-by":"publisher","first-page":"7370","DOI":"10.1038\/s41598-018-24240-2","volume":"8","author":"E Karouzakis","year":"2018","unstructured":"Karouzakis E, Raza K, Kolling C, Buckley CD, Gay S, Filer A, et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci Rep. 2018;8(1):7370. https:\/\/doi.org\/10.1038\/s41598-018-24240-2.","journal-title":"Sci Rep."},{"issue":"5","key":"157_CR10","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1002\/art.39563","volume":"68","author":"Y Araki","year":"2016","unstructured":"Araki Y, Tsuzuki Wada T, Aizaki Y, Sato K, Yokota K, Fujimoto K, et al. Histone methylation and STAT-3 differentially regulate interleukin-6-induced matrix metalloproteinase gene activation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 2016;68(5):1111\u201323. https:\/\/doi.org\/10.1002\/art.39563.","journal-title":"Arthritis Rheumatol."},{"key":"157_CR11","doi-asserted-by":"publisher","unstructured":"Wada TT, Araki Y, Sato K, Aizaki Y, Yokota K, Kim YT, et al. Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts. Biochem Biophys Res Commun. 2014;444(4):682-686. doi: https:\/\/doi.org\/10.1016\/j.bbrc.2014.01.195.","DOI":"10.1016\/j.bbrc.2014.01.195"},{"issue":"10","key":"157_CR12","doi-asserted-by":"publisher","first-page":"4945","DOI":"10.4049\/jimmunol.1400066","volume":"193","author":"E Karouzakis","year":"2014","unstructured":"Karouzakis E, Trenkmann M, Gay RE, Michel BA, Gay S, Neidhart M. Epigenome analysis reveals TBX5 as a novel transcription factor involved in the activation of rheumatoid arthritis synovial fibroblasts. J Immunol. 2014;193(10):4945\u201351. https:\/\/doi.org\/10.4049\/jimmunol.1400066.","journal-title":"J Immunol."},{"issue":"9","key":"157_CR13","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1136\/annrheumdis-2018-214783","volume":"78","author":"C Loh","year":"2019","unstructured":"Loh C, Park SH, Lee A, Yuan R, Ivashkiv LB, Kalliolias GD. TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis. Ann Rheum Dis. 2019;78(9):1205\u201314. https:\/\/doi.org\/10.1136\/annrheumdis-2018-214783.","journal-title":"Ann Rheum Dis."},{"issue":"2","key":"157_CR14","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1136\/annrheumdis-2014-205635","volume":"75","author":"C Angiolilli","year":"2016","unstructured":"Angiolilli C, Grabiec AM, Ferguson BS, Ospelt C, Malvar Fernandez B, van Es IE, et al. Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Ann Rheum Dis. 2016;75(2):430\u20138. https:\/\/doi.org\/10.1136\/annrheumdis-2014-205635.","journal-title":"Ann Rheum Dis."},{"issue":"1","key":"157_CR15","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1136\/annrheumdis-2015-209064","volume":"76","author":"C Angiolilli","year":"2017","unstructured":"Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, Garcia S, et al. Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann Rheum Dis. 2017;76(1):277\u201385. https:\/\/doi.org\/10.1136\/annrheumdis-2015-209064.","journal-title":"Ann Rheum Dis."},{"issue":"4","key":"157_CR16","doi-asserted-by":"publisher","first-page":"e0124254","DOI":"10.1371\/journal.pone.0124254","volume":"10","author":"JW Whitaker","year":"2015","unstructured":"Whitaker JW, Boyle DL, Bartok B, Ball ST, Gay S, Wang W, et al. Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets. Plos One. 2015;10(4):e0124254. https:\/\/doi.org\/10.1371\/journal.pone.0124254.","journal-title":"Plos One."},{"issue":"11","key":"157_CR17","doi-asserted-by":"publisher","first-page":"2637","DOI":"10.1002\/art.39746","volume":"68","author":"D Hammaker","year":"2016","unstructured":"Hammaker D, Whitaker JW, Maeshima K, Boyle DL, Ekwall AH, Wang W, et al. LBH gene transcription regulation by the interplay of an enhancer risk allele and DNA methylation in rheumatoid arthritis. Arthritis Rheumatol. 2016;68(11):2637\u201345. https:\/\/doi.org\/10.1002\/art.39746.","journal-title":"Arthritis Rheumatol."},{"issue":"5","key":"157_CR18","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1002\/art.37872","volume":"65","author":"SM Stanford","year":"2013","unstructured":"Stanford SM, Maestre MF, Campbell AM, Bartok B, Kiosses WB, Boyle DL, et al. Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and survival. Arthritis Rheum. 2013;65(5):1171\u201380. https:\/\/doi.org\/10.1002\/art.37872.","journal-title":"Arthritis Rheum."},{"key":"157_CR19","doi-asserted-by":"publisher","unstructured":"Maeshima K, Stanford SM, Hammaker D, Sacchetti C, Zeng LF, Ai R, et al. Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight. 2016;1(7). https:\/\/doi.org\/10.1172\/jci.insight.86580.","DOI":"10.1172\/jci.insight.86580"},{"issue":"1","key":"157_CR20","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1038\/s41467-018-04310-9","volume":"9","author":"R Ai","year":"2018","unstructured":"Ai R, Laragione T, Hammaker D, Boyle DL, Wildberg A, Maeshima K, et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun. 2018;9(1):1921. https:\/\/doi.org\/10.1038\/s41467-018-04310-9.","journal-title":"Nat Commun."},{"issue":"1","key":"157_CR21","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/s41467-018-02892-y","volume":"9","author":"F Mizoguchi","year":"2018","unstructured":"Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun. 2018;9(1):789. https:\/\/doi.org\/10.1038\/s41467-018-02892-y.","journal-title":"Nat Commun."},{"issue":"7760","key":"157_CR22","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41586-019-1263-7","volume":"570","author":"AP Croft","year":"2019","unstructured":"Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570(7760):246\u201351. https:\/\/doi.org\/10.1038\/s41586-019-1263-7.","journal-title":"Nature."},{"issue":"7811","key":"157_CR23","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41586-020-2222-z","volume":"582","author":"K Wei","year":"2020","unstructured":"Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582(7811):259\u201364. https:\/\/doi.org\/10.1038\/s41586-020-2222-z.","journal-title":"Nature."},{"issue":"9","key":"157_CR24","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1002\/1529-0131(200109)44:9<2176::aid-art371>3.0.co;2-4","volume":"44","author":"Y Katz","year":"2001","unstructured":"Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1, 6, and 8 in skin and synovial fibroblasts: a possible role as a \u201cfine-tuning cytokine\u201d in inflammation processes. Arthritis Rheum. 2001;44(9):2176\u201384. https:\/\/doi.org\/10.1002\/1529-0131(200109)44:9<2176::aid-art371>3.0.co;2-4.","journal-title":"Arthritis Rheum."},{"key":"157_CR25","doi-asserted-by":"publisher","unstructured":"Tsuchiya H, Ota M, Sumitomo S, Ishigaki K, Suzuki A, Sakata T, et al. Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis. Annals of the rheumatic diseases. 2020. https:\/\/doi.org\/10.1136\/annrheumdis-2020-218189.","DOI":"10.1136\/annrheumdis-2020-218189"},{"issue":"2","key":"157_CR26","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.cell.2013.03.035","volume":"153","author":"WA Whyte","year":"2013","unstructured":"Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307\u201319. https:\/\/doi.org\/10.1016\/j.cell.2013.03.035.","journal-title":"Cell."}],"container-title":["Inflammation and Regeneration"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s41232-021-00157-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s41232-021-00157-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s41232-021-00157-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:07:33Z","timestamp":1614557253000},"score":1,"resource":{"primary":{"URL":"https:\/\/inflammregen.biomedcentral.com\/articles\/10.1186\/s41232-021-00157-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,1]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["157"],"URL":"https:\/\/doi.org\/10.1186\/s41232-021-00157-8","relation":{},"ISSN":["1880-8190"],"issn-type":[{"value":"1880-8190","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,1]]},"assertion":[{"value":"15 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7"}}