{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:30:21Z","timestamp":1786977021404,"version":"build-2736575974"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T00:00:00Z","timestamp":1551830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010AT\u2010005520"],"award-info":[{"award-number":["R01\u2010AT\u2010005520"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010AT\u2010007373"],"award-info":[{"award-number":["R01\u2010AT\u2010007373"]}],"id":[{"id":"10.13039\/100000002","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":[[2019,4]]},"abstract":"\n Objective<\/jats:title>\n \n Cytokine expression is tightly regulated posttranscriptionally, but high levels of interleukin\u20106 (\n IL<\/jats:styled-content>\n \u20106) in patients with osteoarthritis (\n OA<\/jats:styled-content>\n ) indicate that regulatory mechanisms are disrupted in this disorder. The enzyme\n ZCCHC<\/jats:styled-content>\n 6 (zinc\u2010finger\n CCHC<\/jats:styled-content>\n domain\u2013containing protein 6;\n TUT<\/jats:styled-content>\n \u20107) has been implicated in posttranscriptional regulation of inflammatory cytokine expression, but its role in\n OA<\/jats:styled-content>\n pathogenesis is unknown. The present study was undertaken to investigate whether\n ZCCHC<\/jats:styled-content>\n 6 directs the expression of\n IL<\/jats:styled-content>\n \u20106 and influences\n OA<\/jats:styled-content>\n pathogenesis in vivo.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Human and mouse chondrocytes were stimulated with recombinant\n IL<\/jats:styled-content>\n \u20101\u03b2. Expression of\n ZCCHC<\/jats:styled-content>\n 6 in human chondrocytes was knocked down using small interfering\n RNA<\/jats:styled-content>\n s.\n IL<\/jats:styled-content>\n \u20106 transcript stability was determined by actinomycin D chase, and 3\u2032\u2010uridylation of micro\n RNA<\/jats:styled-content>\n s was determined by deep sequencing. Zcchc6\n \u2212\/\u2212<\/jats:sup>\n mice were produced by gene targeting.\n OA<\/jats:styled-content>\n was surgically induced in the knee joints of mice, and disease severity was scored using a semiquantitative grading system.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n ZCCHC<\/jats:styled-content>\n 6 was markedly up\u2010regulated in damaged cartilage from human\n OA<\/jats:styled-content>\n patients and from wild\u2010type mice with surgically induced\n OA<\/jats:styled-content>\n . Overexpression of\n ZCCHC<\/jats:styled-content>\n 6 induced the expression of\n IL<\/jats:styled-content>\n \u20106, and its knockdown reduced\n IL<\/jats:styled-content>\n \u20106 transcript stability and\n IL<\/jats:styled-content>\n \u20101\u03b2\u2013induced\n IL<\/jats:styled-content>\n \u20106 expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6\n \u2212\/\u2212<\/jats:sup>\n mouse chondrocytes rescued the\n IL<\/jats:styled-content>\n \u20101\u03b2\u2013induced\n IL<\/jats:styled-content>\n \u20106 expression. Knockdown of\n ZCCHC<\/jats:styled-content>\n 6 reduced the population of micro\u2010\n RNA<\/jats:styled-content>\n 26b (miR\u201026b) with 3\u2032\u2010uridylation by 60%. Zcchc6\n \u2212\/\u2212<\/jats:sup>\n mice with surgically induced\n OA<\/jats:styled-content>\n produced low levels of\n IL<\/jats:styled-content>\n \u20106 and exhibited reduced cartilage damage and synovitis in the joints.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These findings indicate that\n ZCCHC<\/jats:styled-content>\n 6 enhances\n IL<\/jats:styled-content>\n \u20106 expression in chondrocytes through transcript stabilization and by uridylating miR\u201026b, which abrogates repression of\n IL<\/jats:styled-content>\n \u20106. Inhibition of\n IL<\/jats:styled-content>\n \u20106 expression and significantly reduced\n OA<\/jats:styled-content>\n severity in Zcchc6\n \u2212\/\u2212<\/jats:sup>\n mice identify\n ZCCHC<\/jats:styled-content>\n 6 as a novel therapeutic target to inhibit disease pathogenesis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.40751","type":"journal-article","created":{"date-parts":[[2018,10,10]],"date-time":"2018-10-10T03:31:07Z","timestamp":1539142267000},"page":"583-593","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Genetic Inactivation of\n ZCCHC<\/scp>\n 6 Suppresses Interleukin\u20106 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice"],"prefix":"10.1002","volume":"71","author":[{"given":"Mohammad Y.","family":"Ansari","sequence":"first","affiliation":[{"name":"Northeast Ohio Medical University Rootstown"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazir M.","family":"Khan","sequence":"additional","affiliation":[{"name":"Northeast Ohio Medical University Rootstown"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nashrah","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Northeast Ohio Medical University, Rootstown, and Kent State University Kent Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Green","sequence":"additional","affiliation":[{"name":"Northeast Ohio Medical University Rootstown"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Novak","sequence":"additional","affiliation":[{"name":"Northeast Ohio Medical University Rootstown"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3506-6133","authenticated-orcid":false,"given":"Tariq M.","family":"Haqqi","sequence":"additional","affiliation":[{"name":"Northeast Ohio Medical University 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