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首页> 外文学位 >Role du facteur de transcription PITX1 dans la pathogenese de l'arthrose.
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Role du facteur de transcription PITX1 dans la pathogenese de l'arthrose.

机译：转录因子PITX1在骨关节炎发病机理中的作用。

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Osteoarthritis (OA) is one of the most common age-related chronic disorders. The multiplicity of loci identified in OA linkage studies and the large number of associated SNPs suggests that many molecular pathways are involved in OA pathogenesis. Most of these pathways share common features with the process of endochondral ossification, normally occuring during embryogenesis. Cartilage degradation and the presence of osteophytes, hallmarks of OA, could be attributable to the reinitiation of this process. One gene that has surfaced both in OA and in musculoskeletal development is PITX1. Contrary to its original moniker, PITX1 is expressed in many tissues beyond the pituitary gland, including bone, cartilage, muscle and fibroblast cells. Pitx1 is considered as a master regulator of hindlimb identity and its complete inactivation in mice leads to a forelimb-like phenotype. Less severe, its partial inactivation results in early OA symptoms in aging mice. In humans, loss of PITX1 expression is observed in OA cartilage concomitantly with the upregulation of EXTL3, REG1 and PARP1. The association between these proteins and tissue regeneration is consistent with the biosynthesis phase initially taking place in OA cartilage. The dose-dependent relationship between PITX1 and cell proliferation supports the view that low PITX1 expression levels are necessary for chondrocytes to proliferate. Conversely, high levels of PITX1 would prevent proliferation and be required to maintain a differentiated state in normal articular chondrocytes. The regulation of PITX1 gene is of particular interest since it could help to better understand its role in osteoarthritis pathogenesis and in the process of endochondral ossification. Search for mechanisms responsible for the downregulation of PITX1 in OA led to the identification of prohibitin (PHB1) bound to its distal promoter region. PHB1 is a mitochondrial marker but its presence in chondrocytes nuclei seems to correlate with the initiation stage of OA. This discovery could impact diagnosis as well as possible treatments for osteoarthritis.
机译：骨关节炎（OA）是最常见的与年龄相关的慢性疾病之一。在OA连锁研究中鉴定出的基因座的多样性以及大量相关的SNP提示OA发病机理涉及许多分子途径。这些途径中的大多数与软骨内骨化过程具有共同的特征，通常发生在胚胎发生过程中。软骨退化和骨赘的存在（OA的标志）可能归因于这一过程的重新开始。 PITX1是在OA和肌肉骨骼发育中均已出现的一种基因。与最初的绰号相反，PITX1在垂体以外的许多组织中表达，包括骨，软骨，肌肉和成纤维细胞。 Pitx1被认为是后肢身份的主要调节器，其在小鼠中的完全失活会导致前肢样表型。不那么严重，它的部分失活导致衰老小鼠出现早期OA症状。在人类中，伴随着EXTL3，REG1和PARP1的上调，在OA软骨中观察到了PITX1表达的丧失。这些蛋白质与组织再生之间的联系与最初在OA软骨中发生的生物合成阶段相一致。 PITX1与细胞增殖之间的剂量依赖性关系支持以下观点，即低PITX1表达水平是软骨细胞增殖所必需的。相反，高水平的PITX1将阻止增殖，需要维持正常关节软骨细胞的分化状态。 PITX1基因的调节特别令人感兴趣，因为它可以帮助更好地了解其在骨关节炎发病机理和软骨内骨化过程中的作用。寻找导致OA中PITX1下调的机制，导致鉴定了与其远端启动子区域结合的禁止素（PHB1）。 PHB1是线粒体的标志物，但它在软骨细胞核中的存在似乎与OA的起始阶段有关。这一发现可能会影响骨关节炎的诊断以及可能的治疗方法。

著录项

  • 作者

    Picard, Cynthia.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Chemistry Biochemistry.;Biology Molecular.;Health Sciences Aging.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 254 p.
  • 总页数 254
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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