{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:06:44Z","timestamp":1760242004806,"version":"build-2065373602"},"reference-count":12,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T00:00:00Z","timestamp":1543536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Santen Pharmaceutical Co., Ltd.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"the Japanese Ministry of Education, Culture, Sports, Science, and Technology","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"the Japanese Ministry of Health, Labor, and Welfare","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"MEXT-Supported Program for the Strategic Research Foundation at Private Universities","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1\/serum amyloid A-like 1 (SPACIA1\/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). SPACIA1\/SAAL1-deficient mice were generated and used to create mouse models of CIA in mild or severe disease conditions. Cell cycle-related genes, whose expression levels were affected by SPACIA1\/SAAL1 small interfering RNA (siRNA), were screened. Transcriptional and post-transcriptional effects of SPACIA1\/SAAL1 siRNA on cyclin-dependent kinase (cdk) 6 gene expression were investigated in human RASFs. SPACIA1\/SAAL1-deficient mice showed later onset and slower progression of CIA than wild-type mice in severe disease conditions, but not in mild conditions. Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1\/SAAL1 siRNA at the post-transcriptional level. The exacerbation of CIA depends on SPACIA1\/SAAL1 expression, although CIA also progresses slowly in the absence of SPACIA1\/SAAL1. The CDK6, expression of which is up-regulated by the SPACIA1\/SAAL1 expression, might be a critical factor in the exacerbation of CIA.<\/jats:p>","DOI":"10.3390\/ijms19123828","type":"journal-article","created":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T12:13:17Z","timestamp":1543579997000},"page":"3828","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SPACIA1\/SAAL1 Deletion Results in a Moderate Delay in Collagen-Induced Arthritis Activity, along with mRNA Decay of Cyclin-dependent Kinase 6 Gene"],"prefix":"10.3390","volume":"19","author":[{"given":"Ryoji","family":"Fujii","sequence":"first","affiliation":[{"name":"Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa 216-8512, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rie","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa 216-8512, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoo","family":"Sato","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa 216-8512, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iwao","family":"Seki","sequence":"additional","affiliation":[{"name":"AYUMI Pharmaceutical Corporation, Kyoto 612-8374, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Konomi","sequence":"additional","affiliation":[{"name":"Santen Pharmaceutical Co., Ltd., Osaka 533-8651, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Aono","sequence":"additional","affiliation":[{"name":"AYUMI Pharmaceutical Corporation, Kyoto 612-8374, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisateru","family":"Niki","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Yudoh","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa 216-8512, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kusuki","family":"Nishioka","sequence":"additional","affiliation":[{"name":"Global Health Innovation Policy Program (GHIPP), National Graduate Institute for Policy Studies (GRIPS), Tokyo 106-8677, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiro","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa 216-8512, Japan"},{"name":"Institute of Medical Science, Tokyo Medical University, Tokyo 160-8402, Japan"},{"name":"Misato Marine Hospital, Kochi 781-0112, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1056\/NEJM199005033221805","article-title":"Rheumatoid arthritis. 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Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.4049\/jimmunol.180.3.1954","article-title":"Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors","volume":"180","author":"Sekine","year":"2008","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1136\/annrheumdis-2014-205566","article-title":"Cell cycle regulation therapy combined with cytokine blockade enhances antiarthritic effects without increasing immune suppression","volume":"75","author":"Hosoya","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1002\/art.30617","article-title":"Overexpression of SPACIA1\/SAAL1, a newly identified gene that is involved in synoviocyte proliferation, accelerates the progression of synovitis in mice and humans","volume":"63","author":"Sato","year":"2011","journal-title":"Arthritis Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12935-017-0382-1","article-title":"TNF\u03b1 sensitizes chemotherapy and radiotherapy against breast cancer cells","volume":"17","author":"Wu","year":"2017","journal-title":"Cancer Cell Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Thomas, S., Fisher, K.H., Snowden, J.A., Danson, S.J., Brown, S., and Zeidler, M.P. (2015). Methotrexate Is a JAK\/STAT Pathway Inhibitor. 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