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Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro.

机译：在人类破骨细胞模型中调节肿瘤坏死因子相关的凋亡诱导配体（TRAIL）受体。

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摘要

We have previously shown that osteoclasts (OCLs) from multiple myeloma (MM) specimens vary from healthy OCLs in their expression of the TRAIL receptors. TRAIL (TNF-Related Apoptosis-Inducing Ligand), a member of the TNF superfamily, has been shown to induce apoptosis in cells by binding receptors DR4 and DR5, but not DcR1 and DcR2, its decoy receptors, which lack the necessary internal death domain. The observed modulation of these receptors may confer a resistance to apoptosis in the MM environment, and could be related to the cytokine pattern that primarily involves the resorption promoting Receptor Activator of NF-κB Ligand (RANKL) and Macrophage Inflammatory Protein 1 (MIP-1α). The aim of our study was to determine which cytokines present in the disease might be responsible for this modulation. In long term cultures of OCL precursors from cord blood in the presence of M-CSF and RANKL, multinucleated cells (MNCs) that express OCL markers form, and can resorb bone. Through immunocytochemistry we showed that these MNCs can express all four TRAIL receptors. By stimulating with various cytokines (RANKL, MIP-1α, Transforming Factor β (TGFβ), osteoprotegerin (OPG), TRAIL), and parathyroid hormone (PTH) in OCL cultures, we were able to observe receptor modulation at the mRNA level using real time PCR, the protein level using Western blot analysis, and cell surface expression via immunocytochemistry. To determine if these changes translated to a difference in resistance to apoptosis, cells treated with with apoptosis-inducing levels of TRAIL after 5 days of stimulation with the selected cytokines were evaluated via TUNEL to quantify apoptosis. While no correlation has yet been established between the observed receptor modification and apoptosis induction, sample size is a factor, and further tests will be performed. Our results suggest the possibility that TRAIL receptor modification is induced by multiple cytokines present in bone diseases, capable of altering both the susceptibility and resistance pathways in osteoclasts. By potentially prolonging the lifespan of the OCL, these regulatory influences may ultimately be contributory factors to the augmentation of resorption in the micro-environment of bone resorptive diseases like multiple myeloma, Paget's disease of bone, or osteoporosis.;KEY WORDS: Osteoclast, Apoptosis, TRAIL, Resorption.
机译：先前我们已经表明，来自多发性骨髓瘤（MM）标本的破骨细胞（OCL）与健康OCL的TRAIL受体表达有所不同。 TRAIL（TNF相关凋亡诱导配体）是TNF超家族的一员，已被证明可通过结合受体DR4和DR5诱导细胞凋亡，但不能结合诱饵受体DcR1和DcR2，后者缺乏必要的内部死亡域。 。观察到的这些受体的调节可能赋予MM环境中对细胞凋亡的抗性，并且可能与主要涉及NF-κB配体的吸收促进受体激活剂（RANKL）和巨噬细胞炎性蛋白1（MIP-1α）的细胞因子模式有关。 ）。我们研究的目的是确定疾病中存在的哪些细胞因子可能是这种调节的原因。在M-CSF和RANKL存在下，从脐带血中长期培养OCL前体的过程中，表达OCL标记的多核细胞（MNC）形成并可以吸收骨骼。通过免疫细胞化学，我们表明这些MNC可以表达所有四个TRAIL受体。通过在OCL培养物中刺激各种细胞因子（RANKL，MIP-1α，转化因子β（TGFβ），骨保护素（OPG），TRAIL）和甲状旁腺激素（PTH），我们能够使用真实的细胞在mRNA水平上观察受体的调节。实时PCR，蛋白质印迹分析（通过蛋白质印迹分析）和细胞表面表达（通过免疫细胞化学分析）。为了确定这些变化是否转化为对细胞凋亡的抵抗力的差异，通过TUNEL评估用所选细胞因子刺激5天后用诱导细胞凋亡的TRAIL水平处理的细胞，以量化细胞凋亡。虽然在观察到的受体修饰和凋亡诱导之间尚未建立相关性，但样本量是一个因素，将进行进一步的测试。我们的结果表明，TRAIL受体修饰可能是由骨骼疾病中存在的多种细胞因子诱导的，能够改变破骨细胞的敏感性和耐药性途径。通过潜在地延长OCL的寿命，这些调节影响最终可能是增加骨吸收性疾病（如多发性骨髓瘤，佩吉特氏骨病或骨质疏松症）的微环境中吸收的促进因素。关键词：破骨细胞，细胞凋亡，TRAIL，吸收。

著录项

  • 作者

    McManus, Stephen.;

  • 作者单位

    Universite de Sherbrooke (Canada).;

  • 授予单位 Universite de Sherbrooke (Canada).;
  • 学科 Health Sciences Immunology.
  • 学位 M.Sc.
  • 年度 2011
  • 页码 128 p.
  • 总页数 128
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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