{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:55:50Z","timestamp":1779915350666,"version":"3.53.1"},"reference-count":34,"publisher":"BMJ","issue":"2","funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI Grant Numbers JP17K08798"],"award-info":[{"award-number":["KAKENHI Grant Numbers JP17K08798"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI Grant Numbers JP17K16217"],"award-info":[{"award-number":["KAKENHI Grant Numbers JP17K16217"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI Grant Numbers JP21590448"],"award-info":[{"award-number":["KAKENHI Grant Numbers JP21590448"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2019,5,23]]},"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Animal models for human diseases are especially valuable for clarifying molecular mechanisms before or around the onset. As a model for rheumatoid arthritis (RA), we utilise knock-in mice gp130F759. They have a Y759F mutation in gp130, a common receptor subunit for interleukin 6 (IL-6) family cytokines. Definitive arthritis develops around 8 months old and the incidence reaches 100% around 1\u2009year old. Careful examination in the clinical course revealed very subtle resistance in flexibility of joints at 5 months old. Therefore, pathophysiological changes in gp130F759 were examined to dissect molecular mechanisms for preclinical phase of RA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Severity of arthritis in gp130F759 was evaluated with a clinical score system and histological quantification. Serum cytokines, autoantibodies and C reactive protein (CRP) were measured. Changes in the synovium were analysed by real-time PCR, flow cytometry and immunohistochemistry.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Around 5 months old, various types of cytokines, rheumatoid factor (RF), anti-circular citrullinated peptide IgM and CRP increased in the sera of gp130F759. Enhancement of neovascularisation, synovial hyperplasia and fibrosis was observed. Also, increases in haematopoietic cells dominated by innate immune cells and gene expression of <jats:italic>Il6<\/jats:italic> and <jats:italic>Padi4<\/jats:italic> were detected in the joints. <jats:italic>Il6<\/jats:italic> was expressed by non-haematopoietic synovial cells, whereas PAD4 protein was detected in the synovial neutrophils. <jats:italic>Padi4<\/jats:italic> is induced in neutrophils in vitro by IL-6. Increases of phospho-STAT3 and PAD4 protein were detected in the synovium. Deletion of IL-6 in gp130F759 normalised the amount of PAD4 protein in the joints.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The IL-6-PAD4 axis operates in the earliest phase of arthritis in gp130F759, implicating it in early RA.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2018-000853","type":"journal-article","created":{"date-parts":[[2019,6,22]],"date-time":"2019-06-22T06:15:20Z","timestamp":1561184120000},"page":"e000853","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis"],"prefix":"10.1136","volume":"5","author":[{"given":"Ayano","family":"Yahagi","sequence":"first","affiliation":[{"name":"Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Saika","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyasu","family":"Hirano","sequence":"additional","affiliation":[{"name":"Rheumatology, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miwa","family":"Takai-Imamura","sequence":"additional","affiliation":[{"name":"R&D Division, Ayumi Pharmaceutical Corp, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumio","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Nara Research and Development Center, Santen Pharmaceutical Co Ltd, Nara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Aono","sequence":"additional","affiliation":[{"name":"R&D Division, Ayumi Pharmaceutical Corp, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Iseki","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Morita","sequence":"additional","affiliation":[{"name":"Rheumatology, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideya","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiko","family":"Saeki","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, National Hospital Organization, Osaka Minami Medical Center, Kawachinagano, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2826-5188","authenticated-orcid":false,"given":"Katsuhiko","family":"Ishihara","sequence":"additional","affiliation":[{"name":"Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2019,6,21]]},"reference":[{"key":"2025090313154524000_5.2.e000853.1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20044"},{"key":"2025090313154524000_5.2.e000853.2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1443.013"},{"key":"2025090313154524000_5.2.e000853.3","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2011.76"},{"key":"2025090313154524000_5.2.e000853.4","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"2025090313154524000_5.2.e000853.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31472-1"},{"key":"2025090313154524000_5.2.e000853.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"2025090313154524000_5.2.e000853.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.02.006"},{"key":"2025090313154524000_5.2.e000853.8","doi-asserted-by":"crossref","unstructured":"Smolen JS , Aletaha D , Barton A , et al . Rheumatoid arthritis. Nat Rev Dis Primers 2018;4.doi:10.1038\/nrdp.2018.1","DOI":"10.1038\/nrdp.2018.1"},{"key":"2025090313154524000_5.2.e000853.9","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10357"},{"key":"2025090313154524000_5.2.e000853.10","doi-asserted-by":"publisher","DOI":"10.1038\/ng1206"},{"key":"2025090313154524000_5.2.e000853.11","doi-asserted-by":"crossref","unstructured":"Suzuki A , Kochi Y , Shoda H , et al . Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice. BMC Musculoskelet Disord 2016;17.doi:10.1186\/s12891-016-1055-2","DOI":"10.1186\/s12891-016-1055-2"},{"key":"2025090313154524000_5.2.e000853.12","doi-asserted-by":"crossref","unstructured":"Seri Y , Shoda H , Suzuki A , et al . Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model. Sci Rep 2015;5.doi:10.1038\/srep13041","DOI":"10.1038\/srep13041"},{"key":"2025090313154524000_5.2.e000853.13","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1002\/art.38393","article-title":"Peptidylarginine deiminase 4 contributes to tumor necrosis factor \u03b1-induced inflammatory arthritis","volume":"66","author":"Shelef","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"2025090313154524000_5.2.e000853.14","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6101(02)00027-8"},{"key":"2025090313154524000_5.2.e000853.15","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0167-4889(02)00321-X","article-title":"Molecular basis of the cell specificity of cytokine action","volume":"1592","author":"Ishihara","year":"2002","journal-title":"Biochim Biophys Acta"},{"key":"2025090313154524000_5.2.e000853.16","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80162-4"},{"key":"2025090313154524000_5.2.e000853.17","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020619"},{"key":"2025090313154524000_5.2.e000853.18","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052187"},{"key":"2025090313154524000_5.2.e000853.19","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxh045"},{"key":"2025090313154524000_5.2.e000853.20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100900"},{"key":"2025090313154524000_5.2.e000853.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.07.018"},{"key":"2025090313154524000_5.2.e000853.22","doi-asserted-by":"crossref","unstructured":"Murakami M , Hirano T . A four-step model for the IL-6 amplifier, a regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases. Front Immunol 2011;2.doi:10.3389\/fimmu.2011.00022","DOI":"10.3389\/fimmu.2011.00022"},{"key":"2025090313154524000_5.2.e000853.23","doi-asserted-by":"publisher","DOI":"10.1038\/368339a0"},{"key":"2025090313154524000_5.2.e000853.24","doi-asserted-by":"publisher","DOI":"10.1679\/aohc.66.123"},{"key":"2025090313154524000_5.2.e000853.25","doi-asserted-by":"publisher","DOI":"10.1186\/ar1751"},{"key":"2025090313154524000_5.2.e000853.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2013.09.108"},{"key":"2025090313154524000_5.2.e000853.27","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.1002467","article-title":"The transcriptional activator Kr\u00fcppel-like factor-6 is required for CNS myelination","volume":"14","author":"Laitman","year":"2016","journal-title":"PLoS Biol"},{"key":"2025090313154524000_5.2.e000853.28","doi-asserted-by":"crossref","unstructured":"Carmona-Rivera C , Carlucci PM , Moore E , et al . Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol 2017;2. doi:doi:10.1126\/sciimmunol.aag3358","DOI":"10.1126\/sciimmunol.aag3358"},{"key":"2025090313154524000_5.2.e000853.29","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.054924"},{"key":"2025090313154524000_5.2.e000853.30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/cyto.b.20452","article-title":"A comparison of multiplex suspension array large-panel kits for profiling cytokines and chemokines in rheumatoid arthritis patients","volume":"76","author":"Khan","year":"2009","journal-title":"Cytometry B Clin Cytom"},{"key":"2025090313154524000_5.2.e000853.31","doi-asserted-by":"publisher","DOI":"10.1002\/art.27638"},{"key":"2025090313154524000_5.2.e000853.32","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Puerta JA , Celis R , Hern\u00e1ndez MV , et al . Differences in synovial fluid cytokine levels but not in synovial tissue cell infiltrate between anti-citrullinated peptide\/protein antibody-positive and -negative rheumatoid arthritis patients. Arthritis Res Ther 2013;15.doi:10.1186\/ar4372","DOI":"10.1186\/ar4372"},{"key":"2025090313154524000_5.2.e000853.33","doi-asserted-by":"publisher","DOI":"10.1002\/art.22055"},{"key":"2025090313154524000_5.2.e000853.34","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206921"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2018-000853","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T20:15:54Z","timestamp":1756930554000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2018-000853"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,6,21]]},"published-print":{"date-parts":[[2019,6]]}},"alternative-id":["10.1136\/rmdopen-2018-000853"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2018-000853","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6]]}}}