{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T14:12:00Z","timestamp":1785507120100,"version":"3.56.0"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T00:00:00Z","timestamp":1596412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["16K19591"],"award-info":[{"award-number":["16K19591"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"Objective<\/jats:title>Optineurin (OPTN<\/jats:styled-content>) is an autophagy adaptor\/receptor that acts as an intrinsic negative regulator of osteoclast differentiation. RANKL<\/jats:styled-content> expressed by rheumatoid arthritis synovial fibroblasts (RASF<\/jats:styled-content>s) is primarily responsible for the development of bone erosions in patients with RA<\/jats:styled-content>. The aim of the present study was to explore the role of OPTN<\/jats:styled-content> in the pathogenesis of joint destruction in RA<\/jats:styled-content>.<\/jats:p><\/jats:sec>Methods<\/jats:title>RASF<\/jats:styled-content>s were left untreated or incubated with tumor necrosis factor (TNF<\/jats:styled-content>) or interferon\u2010\u03b3 (IFN<\/jats:styled-content>\u03b3), and expression of OPTN<\/jats:styled-content> by RASF<\/jats:styled-content>s was analyzed by reverse transcription\u2013quantitative polymerase chain reaction (RT<\/jats:styled-content>\u2010qPCR<\/jats:styled-content>) and Western blotting. Expression of RANKL<\/jats:styled-content> and osteoprotegerin (OPG<\/jats:styled-content>) was evaluated in cultures of OPTN<\/jats:styled-content>\u2010reduced RASF<\/jats:styled-content>s with or without TNF<\/jats:styled-content> or IFN<\/jats:styled-content>\u03b3 treatment. OPTN<\/jats:styled-content>\u2010reduced RASF<\/jats:styled-content>s were cocultured with monocytes and stained for tartrate\u2010resistant acid phosphatase (TRAP<\/jats:styled-content>). I\u03baB\u03b1, NF<\/jats:styled-content>\u2010\u03baB1, and RelA protein levels were measured to evaluate NF<\/jats:styled-content>\u2010\u03baB signaling. Expression of messenger RNA<\/jats:styled-content> (mRNA<\/jats:styled-content>) for matrix metalloproteinase 3 (MMP<\/jats:styled-content>3<\/jats:italic>), interleukin\u20106 (IL<\/jats:styled-content>6<\/jats:italic>), GATA<\/jats:styled-content> binding protein 3 (GATA<\/jats:styled-content>3<\/jats:italic>), carbohydrate sulfotransferase 15 (CHST<\/jats:styled-content>15<\/jats:italic>), hyaluronan synthase 1 (HAS<\/jats:styled-content>1<\/jats:italic>), and GATA<\/jats:styled-content>1<\/jats:italic> was analyzed by RT<\/jats:styled-content>\u2010qPCR<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>In RASF<\/jats:styled-content>s incubated with TNF<\/jats:styled-content> or IFN<\/jats:styled-content>\u03b3, OPTN<\/jats:styled-content> expression was up\u2010regulated and RANKL<\/jats:styled-content> expression was increased, and these effects were further pronounced in OPTN<\/jats:styled-content>\u2010reduced RASF<\/jats:styled-content>s (all P<\/jats:italic> < 0.05 versus controls). OPG mRNA<\/jats:styled-content> levels remained unchanged. Monocytes cocultured with OPTN<\/jats:styled-content>\u2010reduced RASF<\/jats:styled-content>s differentiated to a greater extent into TRAP<\/jats:styled-content>+ multinucleated cells compared to monocytes cocultured with control RASF<\/jats:styled-content>s (P<\/jats:italic> < 0.05). I\u03baB\u03b1 degradation and nuclear NF<\/jats:styled-content>\u2010\u03baB1 expression following TNF<\/jats:styled-content> treatment were both prolonged in OPTN<\/jats:styled-content>\u2010reduced RASF<\/jats:styled-content>s (each P<\/jats:italic> < 0.05 versus controls). MMP<\/jats:styled-content>3 <\/jats:italic>mRNA<\/jats:styled-content> levels were up\u2010regulated, while GATA<\/jats:styled-content>3<\/jats:italic>, CHST<\/jats:styled-content>15<\/jats:italic>, and HAS<\/jats:styled-content>1<\/jats:italic> mRNA<\/jats:styled-content> levels were down\u2010regulated in OPTN<\/jats:styled-content>\u2010reduced RASF<\/jats:styled-content>s (each P<\/jats:italic> < 0.05 versus controls).<\/jats:p><\/jats:sec>Conclusion<\/jats:title>OPTN<\/jats:styled-content> plays a protective role in RA<\/jats:styled-content> when it is up\u2010regulated in RASF<\/jats:styled-content>s in the presence of proinflammatory cytokines. Absence of OPTN<\/jats:styled-content> might worsen RA<\/jats:styled-content> by generating a joint\u2010destructive state, as indicated by evidence of increased RANKL<\/jats:styled-content> expression on RASF<\/jats:styled-content>s and subsequent osteoclast differentiation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41290","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T03:46:49Z","timestamp":1587354409000},"page":"1493-1504","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Protective Role of Optineurin Against Joint Destruction in Rheumatoid Arthritis Synovial Fibroblasts"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6423-7264","authenticated-orcid":false,"given":"Wen Shi","family":"Lee","sequence":"first","affiliation":[{"name":"Hokkaido University, Sapporo, Japan, and Tokyo Medical and Dental University Tokyo 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