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首页> 外文学位 >Statins regulate IL-1beta-induced RANKL and OPG production by human gingival fibroblasts.
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Statins regulate IL-1beta-induced RANKL and OPG production by human gingival fibroblasts.

机译：他汀类药物通过人牙龈成纤维细胞调节IL-1β诱导的RANKL和OPG的产生。

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摘要

Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase competitive inhibitors, also known as statins, are widely used agents for lowering cholesterol and reducing the risk for a heart attack. Recent data suggest that statins influence bone metabolic activity by stimulating new bone formation both in vivo and in vitro. Bone resorption in periodontitis, an inflammatory disease, is orchestrated by the interaction of various cytokines in the inflamed tissue, produced by immune cells and also by resident cells such as human gingival fibroblasts (HGF) and periodontal ligament (PDL) cells. Three molecules, members of the tumor necrosis factor (TNF) ligand and receptor superfamilies, regulate the process of osteoclast formation. The first one, receptor activator for NF-kappaB ligand (RANKL) is expressed on hematopoetic stromal cells and periosteal osteoblasts as well as on HGF and PDL cells. RANKL interacts with its corresponding receptor, RANK, on mononucleated osteoclast precursors and induces their activation to multinuclear bone resorbing osteoclasts. The effects of RANKL are blocked by its soluble decoy receptor, osteoprotegerin (OPG), thus inhibiting osteoclast differentiation, activation and survival. RANKL and OPG are produced by many cells in the body including human gingival fibroblasts and PDL cells. At the moment, no data exist comparing the effect of statins on OPG/ RANKL production by resting and interleukin-1beta (IL-1beta)-stimulated HGF. Objective . The purpose of this project was to evaluate OPG and RANKL production in resting and IL-1beta-stimulated HGFs, and to determine the effect of statins on their production. Methods. Cytotoxicity of statins was determined using an assay that measures the activity of a mitochondrial enzyme. Fibroblasts were preincubated with atorvastatin or simvastatin for 24 hours in serum-free medium, and then incubated without a stimulus or with IL-1beta for 6 days. OPG or RANKL in culture supernatants was measured by specific ELISA. Data were analyzed using ANOVA and Scheffe's F procedure for post hoc comparison. Results. Concentrations of simvastatin or atorvastatin (5 x 10-6 M to 1 x 10-11 M) had no significant effect on the viability of the fibroblasts, after 7 days of exposure. IL-1beta (1 x 10-8 M) increased OPG production significantly at day 1, 3 and 6, while IL-1beta (1 x 10-10 M) increased OPG production significantly only on day 6. There was a trend towards increasing RANKL production with IL-1beta stimulation, but no statistical significance was reached. When they had an effect, the statins tended to increase constitutive OPG and RANKL production and to decrease it in the presence of IL-1beta, but these findings were not statistically significant. Both statins significantly increased the constitutive RANKL/OPG ratio at multiple concentrations. At the highest concentration (5 x 10-6 M), atorvastatin significantly increased the IL-1beta stimulated RANKL/OPG ratio. Conclusion. Under IL-1beta stimulation and in the absence of statins, OPG production by HGFs was increased significantly. Simvastatin and atorvastatin differed minimally in their effects on OPG and RANKL production by resting and IL-1beta-activated HGFs. Both statins increased constitutive RANKL/OPG ratios, a finding suggesting that in the absence of inflammation statins may influence the production of RANKL and OPG by HGFs to favor bone catabolism.
机译：三羟基-3-甲基-戊二酰-CoA（HMG-CoA）还原酶竞争性抑制剂，也称为他汀类，是降低胆固醇和降低心脏病发作风险的广泛使用的药物。最近的数据表明他汀类药物通过在体内和体外刺激新的骨骼形成来影响骨骼的代谢活性。牙周炎（一种炎症性疾病）中的骨吸收是由发炎组织中各种细胞因子的相互作用精心安排的，这些因子由免疫细胞以及人类牙龈成纤维细胞（HGF）和牙周膜（PDL）细胞等常驻细胞产生。肿瘤坏死因子（TNF）配体和受体超家族的三个分子调节破骨细胞的形成过程。第一个是NF-κB配体的受体激活剂（RANKL）在造血基质细胞和骨膜成骨细胞以及HGF和PDL细胞上表达。 RANKL与单核破骨细胞前体上的相应受体RANK相互作用，并诱导其活化为多核骨吸收破骨细胞。 RANKL的作用被其可溶性诱饵受体骨保护蛋白（OPG）所阻断，从而抑制破骨细胞的分化，活化和存活。 RANKL和OPG由体内的许多细胞产生，包括人牙龈成纤维细胞和PDL细胞。目前，尚无数据比较他汀类药物对静息和白介素-1β（IL-1beta）刺激的HGF对OPG / RANKL产生的影响。目标。该项目的目的是评估静息和IL-1β刺激的HGF中OPG和RANKL的产生，并确定他汀类药物对其产生的影响。方法。使用测量线粒体酶活性的测定法测定他汀类药物的细胞毒性。将成纤维细胞与阿托伐他汀或辛伐他汀在无血清培养基中预孵育24小时，然后在无刺激的情况下或与IL-1beta孵育6天。通过特异性ELISA测量培养上清液中的OPG或RANKL。使用ANOVA和Scheffe's F程序对数据进行分析以进行事后比较。结果。暴露7天后，辛伐他汀或阿托伐他汀的浓度（5 x 10-6 M至1 x 10-11 M）对成纤维细胞的生存能力没有显着影响。 IL-1beta（1 x 10-8 M）在第1、3和6天显着增加OPG产量，而IL-1beta（1 x 10-10 M）仅在第6天显着增加OPG产量。 IL-1β刺激的RANKL产生，但未达到统计学意义。当它们起作用时，他汀类药物倾向于增加组成型OPG和RANKL的产生，并在存在IL-1beta的情况下降低其组成，但这些发现在统计学上并不显着。两种他汀类药物在多种浓度下均显着增加了组成型RANKL / OPG比。在最高浓度（5 x 10-6 M）下，阿托伐他汀显着增加了IL-1β刺激的RANKL / OPG比。结论。在IL-1β刺激下和没有他汀类药物的情况下，HGF的OPG产量显着增加。辛伐他汀和阿托伐他汀通过静息和IL-1beta活化的HGF对OPG和RANKL产生的影响差异最小。两种他汀类药物均增加了本构的RANKL / OPG比率，这一发现表明，在没有炎症的情况下，他汀类药物可能会影响HGF促进RANKL和OPG的生成，从而促进骨分解代谢。

著录项

  • 作者

    Jurkowski, Ivelina N.;

  • 作者单位

    The University of Tennessee Health Science Center.;

  • 授予单位 The University of Tennessee Health Science Center.;
  • 学科 Health Sciences Dentistry.
  • 学位 M.D.S.
  • 年度 2010
  • 页码 44 p.
  • 总页数 44
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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