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首页> 外文期刊>BMC Rheumatology >The antifibrotic drug pirfenidone inhibits spondyloarthritis fibroblast-like synoviocytes and osteoblasts in vitro
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The antifibrotic drug pirfenidone inhibits spondyloarthritis fibroblast-like synoviocytes and osteoblasts in vitro

机译：抗纤维化药物吡非尼酮在体外抑制脊椎关节炎的成纤维样滑膜细胞和成骨细胞

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The pathogenesis of spondyloarthritis (SpA) involves both inflammation and new bone formation in the spine. In line with this, the disease has been characterized as both inflammatory and fibrotic. The current treatment dampens inflammation while new bone formation can progress. Therefore, there is an unmet therapeutic need for the treatment of new bone formation in SpA. Fibrosis is mediated by myofibroblasts and new bone formation is the result of increased osteoblast mineralization and decreased osteoclast resorption. Here, we evaluate the potential effect of the newly approved anti-fibrotic agent pirfenidone (PFD) on fibrosis and new bone formation in cell culture models of SpA. Fibroblast-like synoviocytes (FLSs) were isolated from SpA patients (n = 6) while the osteoblast cell line Saos-2 was purchased. The cells were cultured with PFD at 0.25 0.5, or 1.0 mg/ml. The proliferation of FLSs was analyzed with light microscopy and flow cytometry. The differentiation and activation of FLSs was assessed with flow cytometry, a membrane-based antibody array and enzyme-linked immunosorbant assays. The mineralization capacity of osteoblasts was studied with an assay measuring deposition of hydroxyapatite. PFD reduced the Ki67 expression 7.1-fold in untreated FLSs (p = 0.001) and 11.0-fold in FLSs stimulated with transforming growth factor beta (TGFβ), tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) (p = 0.022). There were no statistically significant changes in membrane expression of alpha smooth muscle actin (αSMA), intercellular adhesion molecule 1 (ICAM-1), or human leukocyte antigen DR (HLA-DR). In supernatants from FLSs stimulated with TGFβ, TNFα, and IFNγ, PFD decreased the secretion of 3 of 12 proteins more than 2-fold in the membrane-based antibody array. The changes in secretion of monocyte chemoattractant protein 1 (MCP-1) and chitinase-3-like protein 1 (CHI3L1, YKL-40) were validated with ELISA. PFD decreased the secretion of both Dickkopf-related protein 1 (DKK1) (p = 0.006) and osteoprotegerin (OPG) (p = 0.02) by SpA FLSs stimulated with TGFβ, TNFα, and IFNγ. Finally, PFD inhibited the deposition of hydroxyapatite by osteoblasts in a dose-dependent manner (p = 0.0001). PFD inhibited SpA FLS proliferation and function and osteoblast mineralization in vitro. This encourages studies of the in vivo effect of PFD in SpA.
机译：脊柱关节炎（SpA）的发病机制涉及脊柱的炎症和新骨形成。与此相一致，该疾病被表征为炎性和纤维化。当前的治疗可以减轻炎症，同时可以促进新的骨骼形成。因此，对于SpA中新骨形成的治疗存在未满足的治疗需求。纤维化是由成肌纤维细胞介导的，新的骨形成是成骨细胞矿化增加和破骨细胞吸收减少的结果。在这里，我们评估了新批准的抗纤维化剂吡非尼酮（PFD）对SpA细胞培养模型中纤维化和新骨形成的潜在影响。在购买成骨细胞系Saos-2的同时，从SpA患者中分离出成纤维样滑膜细胞（nblast = 6）。用PFDF以0.25 0.5或1.0 mg / ml培养细胞。用光学显微镜和流式细胞术分析FLS的增殖。 FLS的分化和激活通过流式细胞仪，基于膜的抗体阵列和酶联免疫吸附法进行评估。用测定羟基磷灰石沉积的试验研究了成骨细胞的矿化能力。 PFD使未治疗的FLS中Ki67表达降低7.1倍（p = 0.001），而用转化生长因子β（TGFβ），肿瘤坏死因子α（TNFα）和干扰素γ（IFNγ）刺激的FLS降低Ki67表达（p = 0.022） ）。 α平滑肌肌动蛋白（αSMA），细胞间粘附分子1（ICAM-1）或人白细胞抗原DR（HLA-DR）的膜表达没有统计学上的显着变化。在TGFβ，TNFα和IFNγ刺激的FLS上清液中，PFD减少了基于膜的抗体阵列中12种蛋白质中的3种的分泌，是其2倍以上。 ELISA验证了单核细胞趋化蛋白1（MCP-1）和几丁质酶3样蛋白1（CHI3L1，YKL-40）的分泌变化。 PFD通过TGFβ，TNFα和IFNγ刺激的SpA FLS减少Dickkopf相关蛋白1（DKK1）（p（= 0.006）和骨保护素（OPG）（p = 0.02）的分泌。最后，PFD以成剂量依赖性的方式抑制成骨细胞对羟基磷灰石的沉积（p = 0.0001）。 PFD在体外抑制SpA FLS增殖和功能以及成骨细胞矿化。这鼓励了对SpA中PFD体内作用的研究。

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