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首页> 外文期刊>Arthritis and Rheumatism >Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption.
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Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption.

机译：人和小鼠滑膜成纤维细胞对细胞因子控制的RANKL和骨保护素的表达：成纤维细胞介导的病理性骨吸收。

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OBJECTIVE: To determine whether proinflammatory cytokine treatment or the complete absence of select cytokines modulates the expression of RANKL and osteoprotegerin (OPG) in synovial fibroblasts. METHODS: Fibroblasts were isolated from normal and rheumatoid human synovium and from normal or arthritic joints of wild-type and cytokine gene-deficient (interleukin-4-knockout [IL-4 (-/-)] and interferon-gamma-knockout [IFNgamma (-/-)]) mice. Fibroblasts were stimulated with proinflammatory cytokines (tumor necrosis factor alpha [TNFalpha], IL-1beta, and IL-17) or antiosteoclastogenic cytokines (IL-4 and IFNgamma), alone or in combination, and the expression of RANKL and OPG was measured. RESULTS: Proinflammatory cytokine-stimulated fibroblasts from rheumatoid and arthritic mouse joints expressed higher levels of RANKL and OPG than those from normal joints. IL-4 suppressed RANKL expression and increased OPG expression, IFNgamma reduced the production of both RANKL and OPG, and IL-17 had only a modest effect on the expression of RANKL or OPG. Additive effects of combination treatment (TNFalpha/IL-17 or IL-1beta/IL-17) were observed only in the human system. Extensive destruction was observed in the arthritic joints of IL-4 (-/-) mice, with a corresponding upward shift of the RANKL:OPG ratios. However, an IL-17 deficiency did not attenuate arthritis or reduce bone resorption. CONCLUSION: Proinflammatory cytokines induce the expression of RANKL and OPG in both human and murine synovial fibroblasts. The RANKL:OPG ratios are shifted in favor of bone protection by IL-4 treatment, and, to a lesser extent, by IFNgamma treatment. Unexpectedly, an IL-17 deficiency alone does not induce reduced inflammatory bone destruction. Our results suggest that synovial fibroblasts may significantly contribute to bone resorption through modulation of RANKL and OPG production in a cytokine-rich milieu of inflamed joints.
机译：目的：确定促炎性细胞因子治疗或完全不存在某些选择的细胞因子是否能调节滑膜成纤维细胞中RANKL和骨保护素（OPG）的表达。方法：从正常和类风湿性人滑膜，野生型和细胞因子基因缺陷型（白介素4敲除[IL-4（-/-）]和干扰素-γ-敲除[IFNγ]的正常或关节炎关节中分离成纤维细胞） （-/-）]） 老鼠。单独或组合用促炎细胞因子（肿瘤坏死因子αTNFα，IL-1β和IL-17）或抗破骨细胞生成细胞因子（IL-4和IFNγ）刺激成纤维细胞，并测量RANKL和OPG的表达。结果：类风湿和关节炎小鼠关节的促炎细胞因子刺激的成纤维细胞表达的RANKL和OPG水平高于正常关节。 IL-4抑制了RANKL的表达并增加了OPG的表达，IFNgamma降低了RANKL和OPG的产生，而IL-17对RANKL或OPG的表达只有中等程度的影响。仅在人类系统中观察到联合治疗（TNFalpha / IL-17或IL-1beta / IL-17）的加和作用。在IL-4（-/-）小鼠的关节炎关节中观察到广泛的破坏，同时RANKL：OPG比值相应上升。但是，IL-17缺乏症不会减轻关节炎或降低骨吸收。结论：促炎细胞因子诱导人和鼠滑膜成纤维细胞中RANKL和OPG的表达。 RANKL：OPG的比例发生了变化，有利于通过IL-4处理，以及在较小程度上通过IFNgamma处理对骨骼的保护。出乎意料的是，单独的IL-17缺乏并不能减少炎症性骨破坏。我们的结果表明，滑膜成纤维细胞可能通过调节富含炎症因子的细胞因子环境中的RANKL和OPG产生，显着促进骨吸收。

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