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首页> 外文期刊>Arthritis & Rheumatism >The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats
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The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats

机译：蛋白酶体抑制剂硼替佐米可显着影响佐剂性关节炎大鼠的炎症和骨骼疾病

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ObjectiveTo explore the effect of bortezomib in splenocytes and fibroblast-like synoviocytes (FLS) and its in vivo potency in a rat model of adjuvant-induced arthritis (AIA), which resembles human rheumatoid arthritis (RA).MethodsAIA was induced with Freund's complete adjuvant. Splenocyte and FLS proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively. The invasiveness of FLS from rats with AIA was tested in a Transwell system. The pattern of cytokine secretion was evaluated by cytometric bead array in splenocyte supernatants. Bortezomib was administered prophylactically or therapeutically, and arthritis was assessed clinically and histologically. Immunohistochemistry was performed for markers of inflammation and angiogenesis in joints. Hematologic and biochemical parameters were tested in peripheral blood (PB). Representative animals were examined by computed tomography (CT) scanning before and after bortezomib administration. The expression of Toll-like receptor 2 (TLR-2), TLR-3, and TLR-4 in PB and FLS was measured by real-time polymerase chain reaction, and alterations in specific cell populations in PB and spleen were determined by flow cytometry.ResultsIn vitro, bortezomib exhibited significant inhibitory and proapoptotic activity in splenocytes and FLS from rats with AIA, altered the inflammatory cytokine pattern, and reduced the invasiveness of FLS from rats with AIA. In vivo, bortezomib significantly ameliorated disease severity. Remission was associated with improved histology and decreased expression of CD3, CD79a, CD11b, cyclooxygenase 1, and factor VIII in target tissues as well as down-regulation of TLR expression in PB and cultured FLS. CT scanning demonstrated a bone healing effect after treatment.ConclusionOur findings suggest that bortezomib affects AIA in a pleiotropic manner and that this drug may be effective in RA.
机译：目的探讨硼替佐米在佐剂诱导的关节炎（AIA）模型（类似于人类风湿性关节炎（RA））的大鼠模型中对脾细胞和成纤维样滑膜细胞（FLS）的作用及其体内效能。方法。通过放射性掺入和流式细胞术分别测量脾细胞和FLS增殖和凋亡。在Transwell系统中测试了AIA大鼠FLS的侵袭性。通过细胞计数珠阵列评估脾细胞上清液中细胞因子分泌的模式。预防性或治疗性给予硼替佐米，并在临床和组织学上评估关节炎。进行免疫组织化学分析关节炎症和血管生成的标志物。在外周血（PB）中测试血液学和生化参数。在服用硼替佐米之前和之后，通过计算机断层扫描（CT）扫描检查代表性动物。通过实时聚合酶链反应测量PB和FLS中Toll样受体2（TLR-2），TLR-3和TLR-4的表达，并通过流动测定PB和脾脏中特定细胞群的变化结果在体外，硼替佐米对AIA大鼠的脾细胞和FLS具有明显的抑制和促凋亡活性，改变了炎症细胞因子的模式，并降低了AIA大鼠FLS的侵袭性。在体内，硼替佐米可显着改善疾病严重程度。缓解与组织学改善和靶组织中CD3，CD79a，CD11b，环氧合酶1和因子VIII的表达降低以及PB和培养的FLS中TLR表达的下调相关。 CT扫描显示出治疗后的骨愈合效果。结论我们的研究结果表明，硼替佐米以多效性方式影响AIA，该药物可能对RA有效。

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