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首页> 美国卫生研究院文献>Rheumatology (Oxford England) >Optimized alkylated cyclodextrin polysulphates with reduced risks on thromboembolic accidents improve osteoarthritic chondrocyte metabolism
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Optimized alkylated cyclodextrin polysulphates with reduced risks on thromboembolic accidents improve osteoarthritic chondrocyte metabolism

机译：优化的烷基化环糊精多硫酸盐可降低血栓栓塞事故的发生风险改善骨关节炎软骨细胞代谢

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>Objectives. To compare the ability of different cyclodextrin polysulphate (CDPS) derivatives to affect human articular cartilage cell metabolism in vitro.>Methods. OA chondrocytes were cultured in alginate and exposed to 5 µg/ml of 2,3,6-tri-O-methyl-β-cyclodextrin (ME-CD), 2,3-di-O-methyl-6-sulphate-β-cyclodextrin (ME-CD-6-S), 2,6-di-O-methyl-3-sulphate-β-cyclodextrin (ME-CD-3-S), (2-carboxyethyl)-β-CDPS (CE-CDPS), (2-hydroxypropyl)-β-CDPS (HP-CDPS), 6-monoamino-6-monodeoxy-β-CDPS (MA-CDPS) or β-CDPS for 5 days. Effects on IL-1-driven chondrocyte extracellular matrix (ECM) metabolism were assayed by analysis of the accumulation of aggrecan in the interterritorial matrix, IL-6 secretion and qPCR. MA-CDPS, HP-CDPS, CE-CDPS and CDPS were analysed for their in vitro effect on coagulation and their ability to activate platelets in an in vitro assay to detect possible cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies.>Results. The monosulphated cyclodextrins ME-CD-6-S and -3-S failed to affect aggrecan synthesis and IL-6 secretion by the OA chondrocytes. Polysulphated cyclodextrins MA-CDPS, HP-CDPS, CE-CDPS and CDPS at 5 µg/ml concentrations, on the other hand, significantly induced aggrecan production and repressed IL-6 release by the chondrocytes in culture. aPTT and PT for all derivatives were lengthened for polysaccharide concentrations >50 µg/ml. Five micrograms per millilitre of β-CDPS concentrations that significantly modulated ECM ground substance production in vitro did not affect aPTT or PT. Furthermore, CE-CDPS, in contrast to MA-CDPS, HP-CDPS and CDPS, did not significantly activate platelets, suggesting a minimal potential to induce HIT thromboembolic accidents in vivo.>Conclusions. CE-CDPS is a new, structurally adjusted, sulphated β-cyclodextrin derivative with preserved chondroprotective capacity and a promising safety profile.
机译：>目标。比较不同环糊精多硫酸盐（CDPS）衍生物体外影响人关节软骨细胞代谢的能力。>方法。在藻酸盐中培养OA软骨细胞并暴露于5种µg / ml 2,3,6-三-O-甲基-β-环糊精（ME-CD），2,3-二-O-甲基-6-硫酸盐-β-环糊精（ME-CD-6-S ），2,6-二-O-甲基-3-硫酸酯-β-环糊精（ME-CD-3-S），（2-羧乙基）-β-CDPS（CE-CDPS），（2-羟丙基）- β-CDPS（HP-CDPS），6-单氨基-6-单脱氧-β-CDPS（MA-CDPS）或β-CDPS持续5天。通过分析跨膜基质中聚集蛋白聚糖的积累，IL-6分泌和qPCR分析了对IL-1驱动的软骨细胞胞外基质（ECM）代谢的影响。在体外试验中分析了MA-CDPS，HP-CDPS，CE-CDPS和CDPS在体外对凝血的作用及其激活血小板的能力，以检测与肝素诱导的血小板减少症（HIT）抗体可能的交叉反应性。 strong>结果。单硫酸化环糊精ME-CD-6-S和-3-S不能​​影响OA软骨细胞的聚集蛋白聚糖合成和IL-6分泌。另一方面，多硫酸化环糊精MA-CDPS，HP-CDPS，CE-CDPS和CDPS的浓度为5μg/ ml，可显着诱导软骨聚集蛋白聚糖的产生并抑制培养中软骨细胞的IL-6释放。当多糖浓度>50μg/ ml时，所有衍生物的aPTT和PT均延长。在体外显着调节ECM地面物质产生的每毫升β-CDPS浓度为5微克，不会影响aPTT或PT。此外，与MA-CDPS，HP-CDPS和CDPS相比，CE-CDPS不能显着激活血小板，这表明在体内诱发HIT血栓栓塞事故的可能性很小。>结论。 CE-CDPS是一种新的，经过结构调整的硫酸化β-环糊精衍生物，具有保留的软骨保护能力和有希望的安全性。

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