{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:30:18Z","timestamp":1791415818857,"version":"4.3.3"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2017,11,1]],"date-time":"2017-11-01T00:00:00Z","timestamp":1509494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite advances in the treatment of rheumatoid arthritis (RA), currently approved medications can have significant side effects due to their direct immunosuppressive activities. Additionally, current therapies do not address residual synovial inflammation. In this study, we evaluated the role of integrin \u03b19 and its ligand, tenascin-C (Tn-C), on the proliferative and inflammatory response of fibroblast-like synoviocytes (FLSs) from RA patients grown in three-dimensional (3D)\u2013micromass culture. FLSs from osteoarthritis patients, when grown in the 3D-culture system, formed self-directed lining-like structures, whereas FLSs from RA tissues (RA-FLSs) developed an abnormal structure of condensed cellular accumulation reflective of the pathogenic features of RA synovial tissues. Additionally, RA-FLSs grown in 3D culture showed autonomous production of proinflammatory mediators. Predominant expression of \u03b19 and Tn-C was observed in the condensed lining, and knockdown of these molecules abrogated the abnormal lining-like structure formation and suppressed the spontaneous expression of matrix metalloproteinases, IL-6, TNFSF11\/RANKL, and cadherin-11. Disruption of \u03b19 also inhibited expression of Tn-C, suggesting existence of a positive feedback loop in which the engagement of \u03b19 with Tn-C self-amplifies its own signaling and promotes progression of synovial hyperplasia. Depletion of \u03b19 also suppressed the platelet-derived growth factor\u2013induced hyperplastic response of RA-FLSs and blunted the TNF-\u03b1\u2013induced expression of matrix metalloproteinases and IL-6. Finally, \u03b19-blocking Ab also suppressed the formation of the condensed cellular lining by RA-FLSs in 3D cultures in a concentration-related manner. This study demonstrates the central role of \u03b19 in pathogenic behaviors of RA-FLSs and highlights the potential of \u03b19-blocking agents as a nonimmunosuppressive treatment for RA-associated synovitis.<\/jats:p>","DOI":"10.4049\/jimmunol.1700941","type":"journal-article","created":{"date-parts":[[2017,10,17]],"date-time":"2017-10-17T00:40:38Z","timestamp":1508200838000},"page":"3427-3436","source":"Crossref","is-referenced-by-count":32,"title":["Constitutive Activation of Integrin \u03b19 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis"],"prefix":"10.1093","volume":"199","author":[{"given":"Takashi","family":"Emori","sequence":"first","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hirose","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotoko","family":"Ise","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-ichiro","family":"Yomoda","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadanobu","family":"Shinkuma","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yoshitomi","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromu","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Graduate School of Medicine, Kyoto University , Kyoto 606-8507,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motomu","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University , Kyoto 606-8507,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Sugahara","sequence":"additional","affiliation":[{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-1345","authenticated-orcid":false,"given":"Hirotada","family":"Fujita","sequence":"additional","affiliation":[{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4895-1596","authenticated-orcid":false,"given":"Nobuchika","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Morita","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 305-8585,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8062-6529","authenticated-orcid":false,"given":"Shuh","family":"Narumiya","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Aramori","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Kyoto 606-8501,","place":["Japan"]},{"name":"Drug Discovery Research, Astellas Pharma Inc. , Ibaraki 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