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Tumor necrosis factor (TNF)-<jats:italic>\u03b1<\/jats:italic>, a dominant inflammatory mediator in RA pathogenesis, promotes progression of RA symptoms. Prevalence of 1, 25-dihydroxy-vitamin D<jats:sub>3<\/jats:sub> (hereafter termed VD) deficiency is 30\u201363% in patients with RA. Whether VD leads to apoptosis or enhances TNF-<jats:italic>\u03b1<\/jats:italic>-mediated apoptosis in FLSs to ameliorate RA is unclear. To determine this, 10-week-old <jats:italic>CYP27B1-<\/jats:italic>deficient (<jats:italic>CYP27B1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice with collagen-induced arthritis (CIA) were intraperitoneally treated with 1\u2009<jats:italic>\u03bc<\/jats:italic>g\/kg VD every other day for 9 weeks. RA phenotypes were compared between vehicle-treated <jats:italic>CYP27B1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and wild-type CIA mice. Human rheumatoid FLS-MH7A cells were treated with Dulbecco\u2019s modified Eagle\u2019s medium (DMEM) without fetal bovine serum (FBS) for 24\u2009h, then with different concentrations of VD and TNF-<jats:italic>\u03b1<\/jats:italic>, human vitamin D receptor (VDR) siRNA or the p53 pro-apoptotic inhibitor pifithrin-<jats:italic>\u03b1<\/jats:italic>. Apoptosis and p53 pro-apoptotic signaling were analyzed. The 19-week-old vehicle-treated <jats:italic>CYP27B1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> CIA mice had increased cumulative arthritis scores and levels of serous rheumatoid factors and C-reactive protein. They had exacerbated articular cartilage and bone destruction, joint space narrowing, joint stiffness, deformity and dysfunction, synovitis and TNF-<jats:italic>\u03b1<\/jats:italic> secretion, FLS hyperplasia with increased proliferation and decreased apoptosis compared to CIA mice. These RA phenotypes that were aggravated in CIA mice by <jats:italic>CYP27B1<\/jats:italic> deficiency were largely rescued by VD treatment. <jats:italic>In vitro<\/jats:italic>, VD with TNF-<jats:italic>\u03b1<\/jats:italic> treatment upregulated p53 acetylation-mediated apoptosis in MH7A cells by promoting Sirt1 translocation from the nucleus to the cytoplasm. These findings indicated that VD with TNF-<jats:italic>\u03b1<\/jats:italic> protected against RA by promoting apoptosis of FLSs. The results indicated that clinical administration of VD could be a specific therapy to promote FLS apoptosis and prevent RA progression.<\/jats:p>","DOI":"10.1038\/cddis.2016.300","type":"journal-article","created":{"date-parts":[[2016,10,20]],"date-time":"2016-10-20T12:52:47Z","timestamp":1476967967000},"page":"e2423-e2423","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["1, 25-dihydroxy-vitamin D3 with tumor necrosis factor-alpha protects against rheumatoid arthritis by promoting p53 acetylation-mediated apoptosis via Sirt1 in synoviocytes"],"prefix":"10.1038","volume":"7","author":[{"given":"Xin","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjie","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhui","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxin","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengshun","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianliang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,20]]},"reference":[{"key":"BFcddis2016300_CR1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.jaut.2012.05.021","volume":"39","author":"MC Boissier","year":"2012","unstructured":"Boissier MC, Semerano L, Challal S, Saidenberg-Kermanac'h N, Falgarone G . 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