{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:33:27Z","timestamp":1790512407792,"version":"4.1.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangzhou Science and Technology Project","award":["201803010042"],"award-info":[{"award-number":["201803010042"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81671591,81871275,U1401222,81501389,81373182"],"award-info":[{"award-number":["81671591,81871275,U1401222,81501389,81373182"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,8]]},"abstract":"<jats:p>Fibroblast-like synoviocytes (FLSs) play a key role in controlling synovial inflammation and joint destruction in rheumatoid arthritis (RA). The contribution of long noncoding RNAs (lncRNAs) to RA is largely unknown. Here, we show that the lncRNA LINK-A, located mainly in cytoplasm, has higher-than-normal expression in synovial tissues and FLSs from patients with RA. Synovial LINK-A expression was positively correlated with the severity of synovitis in patients with RA. LINK-A knockdown decreased migration, invasion, and expression and secretion of matrix metalloproteinases and proinflammatory cytokines in RA FLSs. Mechanistically, LINK-A controlled RA FLS inflammation and invasion through regulation of tyrosine protein kinase 6\u2013mediated and leucine-rich repeat kinase 2\u2013mediated HIF-1\u03b1. On the other hand, we also demonstrate that LINK-A could bind with microRNA 1262 as a sponge to control RA FLS aggression but not inflammation. Our findings suggest that increased level of LINK-A may contribute to FLS-mediated rheumatoid synovial inflammation and aggression. LINK-A might be a potential therapeutic target for RA.<\/jats:p>","DOI":"10.1172\/jci.insight.146757","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T14:00:50Z","timestamp":1638885650000},"source":"Crossref","is-referenced-by-count":16,"title":["Increased long noncoding RNA LINK-A contributes to rheumatoid synovial inflammation and aggression"],"prefix":"10.1172","volume":"6","author":[{"given":"Jingnan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyu","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiru","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuicui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Guangzhou First People\u2019s Hospital, School of Medicine, South China University of Technology, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1757-572X","authenticated-orcid":true,"given":"Minxi","family":"Lao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maohua","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-0969","authenticated-orcid":true,"given":"Xiaoyan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Guangzhou First People\u2019s Hospital, School of Medicine, South China University of Technology, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuqin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanshi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30173-8"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/08830185.2016.1269175"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew347"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0413-5"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.190"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.04.009"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2017.08.002"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4479"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.011"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.25607"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0849-2"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2020.1747776"},{"issue":"7","key":"B13","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1080\/15548627.2019.1659614","article-title":"ZNNT1 long noncoding RNA induces autophagy to inhibit tumorigenesis of uveal melanoma by regulating key autophagy gene expression","volume":"16","author":"Li","year":"2019","journal-title":"Autophagy"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3295"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313768111"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2478\/jtim-2019-0002"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtauto.2020.100044"},{"issue":"8","key":"B18","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1097\/CM9.0000000000000755","article-title":"Involvement of long non-coding RNAs in the pathogenesis of rheumatoid arthritis","volume":"133","author":"Lao","year":"2020","journal-title":"Chin Med J (Engl)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97965"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.11.024"},{"issue":"27","key":"B21","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1002\/art.21118","article-title":"Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis","volume":"52","author":"Tolboom","year":"2005","journal-title":"Arthritis Rheum"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0162008"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0904068"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13866"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.355"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00702"},{"issue":"6","key":"B27","first-page":"5005","article-title":"LINK-A lncRNA functions in the metastasis of osteosarcoma by upregulating HIF1\u03b1","volume":"17","author":"Zhao","year":"2019","journal-title":"Oncol Lett"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20180936"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.912141"},{"issue":"1","key":"B30","first-page":"119","article-title":"LINK-A lncRNA activates HIF1\u03b1 signaling and inhibits podocyte cell apoptosis in diabetic nephropathy","volume":"18","author":"Yang","year":"2019","journal-title":"Exp Ther Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204105"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200867"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.119776"},{"issue":"1","key":"B34","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-03921-4","article-title":"HIF-1alpha knockdown reduces glycolytic metabolism and induces cell death of human synovial fibroblasts under normoxic conditions","volume":"7","author":"Del Rey","year":"2017","journal-title":"Sci Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/art.40569"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/art.24844"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545784"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096060"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13665-6"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1042\/BST20180463"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201802550R"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.07.014"},{"key":"B43","article-title":"LRP8, modulated by miR-1262, promotes tumour progression and forecasts the prognosis of patients in breast cancer","author":"Li","journal-title":"Arch Physiol Biochem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1078\/0344-0338-5710261"},{"key":"B46","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/978-1-4939-1369-5_11","article-title":"RNA fluorescence in situ hybridization in cultured mammalian cells","volume":"1206","author":"Tripathi","year":"2015","journal-title":"Methods Mol Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1311239111"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/146757\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:41:04Z","timestamp":1779147664000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/146757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":47,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12,8]]},"published-print":{"date-parts":[[2021,12,8]]}},"alternative-id":["10.1172\/jci.insight.146757"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.146757","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]},"article-number":"e146757"}}