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Impaired apoptosis of fibroblast-like synoviocytes (FLSs) causes synovial hyperplasia, facilitating destruction of cartilage and bone in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)- α , a dominant inflammatory mediator in RA pathogenesis, promotes progression of RA symptoms. Prevalence of 1, 25-dihydroxy-vitamin D 3  (hereafter termed VD) deficiency is 30–63% in patients with RA. Whether VD leads to apoptosis or enhances TNF- α -mediated apoptosis in FLSs to ameliorate RA is unclear. To determine this, 10-week-old  CYP27B1- deficient ( CYP27B1  −/− ) mice with collagen-induced arthritis (CIA) were intraperitoneally treated with 1  μ g/kg VD every other day for 9 weeks. RA phenotypes were compared between vehicle-treated  CYP27B1  −/−  and wild-type CIA mice. Human rheumatoid FLS-MH7A cells were treated with Dulbecco's modified Eagle's medium (DMEM) without fetal bovine serum (FBS) for 24 h, then with different concentrations of VD and TNF- α , human vitamin D receptor (VDR) siRNA or the p53 pro-apoptotic inhibitor pifithrin- α . Apoptosis and p53 pro-apoptotic signaling were analyzed. The 19-week-old vehicle-treated  CYP27B1  −/−  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- α  secretion, FLS hyperplasia with increased proliferation and decreased apoptosis compared to CIA mice. These RA phenotypes that were aggravated in CIA mice by  CYP27B1  deficiency were largely rescued by VD treatment.  In vitro , VD with TNF- α  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- α  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.

cell death and disease

1, 25-dihydroxy-vitamin D3 with tumor necrosis factor-alpha protects against rheumatoid arthritis by promoting p53 acetylation-mediated apoptosis via Sirt1 in synoviocytes