1, 25-dihydroxy-vitamin D3 with tumor necrosis factor-alpha protects against rheumatoid arthritis by promoting p53 acetylation-mediated apoptosis via Sirt1 in synoviocytes.
1, 25-dihydroxy-vitamin D3 with tumor necrosis factor-alpha protects against rheumatoid arthritis by promoting p53 acetylation-mediated apoptosis via Sirt1 in synoviocytes.
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1, 25-二羟基维生素 D3 与肿瘤坏死因子-α 通过 Sirt1 促进滑膜细胞中 p53 乙酰化介导的细胞凋亡，从而预防类风湿性关节炎
DOI：
10.1038/cddis.2016.300
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发表时间：
2016-10-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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成纤维细胞样滑膜细胞（FLS）凋亡受损导致滑膜增生，促进类风湿性关节炎（RA）中软骨和骨的破坏。肿瘤坏死因子（TNF）-α是RA发病机制中的主要炎症介质，可促进RA症状的进展。在RA患者中，1，25-二羟维生素D3（以下称为VD）缺乏的患病率为30-63%。VD是否导致FLS中的细胞凋亡或增强TNF-α介导的细胞凋亡以改善RA尚不清楚。为了确定这一点，对患有胶原诱导性关节炎（CIA）的10周龄CYP 27 B1缺陷（CYP 27 B1 −/−）小鼠每隔一天腹腔注射1 μg/kg VD，持续9周。在溶剂处理的CYP 27 B1 −/−和野生型CIA小鼠之间比较RA表型。用不含胎牛血清（FBS）的Dulbecco改良Eagle培养基（DMEM）处理人类风湿FLS-MH 7A细胞24 h，然后加入不同浓度的VD和TNF-α、人维生素D受体（VDR）siRNA或p53促凋亡抑制剂pifithrin-α。分析细胞凋亡和p53促凋亡信号传导。19周龄的CYP 27 B1 −/− CIA小鼠的累积关节炎评分和血清类风湿因子和C反应蛋白水平增加。与CIA小鼠相比，它们加重了关节软骨和骨破坏、关节间隙变窄、关节僵硬、畸形和功能障碍、滑膜炎和TNF-α分泌、FLS增生、增殖增加和凋亡减少。这些RA表型在CIA小鼠中因CYP 27 B1缺乏而加重，但在很大程度上被VD治疗所挽救。在体外，VD联合TNF-α处理通过促进Sirt 1从细胞核转位到细胞质，上调了p53乙酰化介导的MH 7A细胞凋亡。这些结果表明，VD联合TNF-α通过促进FLS的凋亡来保护RA。提示VD临床应用可能是一种促进FLS凋亡、预防RA进展的特异性治疗方法。
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 D3 (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 μg/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.
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