A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease
A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease
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DOI：
10.1038/ng1557
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发表时间：
2005-06-01
期刊：
影响因子：
30.8
通讯作者：
Ikegawa, S
中科院分区：
文献类型：
--
作者：
Seki, S;Kawaguchi, Y;Ikegawa, S
腰椎间盘疾病（LDD）是由腰椎间盘退变引起的。最常见的肌肉骨骼疾病之一（1），LDD具有很强的遗传决定因素（2-4）。使用病例对照关联研究，我们鉴定了CILP中的功能性SNP（1184 T--> C，导致氨基酸取代I395 T），其编码软骨中间层蛋白，其作为LDD易感性的调节剂。CILP在椎间盘中表达丰富，且随着椎间盘退变程度的加重，其表达逐渐增强. CILP与TGF-β 1共定位于椎间盘中的成簇软骨细胞及其区域基质中。CILP通过与TGF-β 1直接相互作用和抑制TGF-β 1信号传导来抑制TGF-β 1介导的软骨基质基因诱导。易感性相关的1184 C等位基因显示出增加的TGF-β 1结合和抑制。因此，我们得出结论，细胞外基质蛋白CILP调节TGF-β信号传导，这种调节在LDD的病因和发病机制中起着至关重要的作用。我们的研究还增加了与TGF-β相关的结缔组织疾病的列表。
Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders(1), LDD has strong genetic determinants(2-4). Using a case-control association study, we identified a functional SNP ( 1184T --> C, resulting in the amino acid substitution I395T) in CILP, which encodes the cartilage intermediate layer protein, that acts as a modulator of LDD susceptibility. CILP was expressed abundantly in intervertebral discs, and its expression increased as disc degeneration progressed. CILP colocalized with TGF-beta 1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-beta 1-mediated induction of cartilage matrix genes through direct interaction with TGF-beta 1 and inhibition of TGF-beta 1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-beta 1. Therefore, we conclude that the extracellular matrix protein CILP regulates TGF-beta signaling and that this regulation has a crucial role in the etiology and pathogenesis of LDD. Our study also adds to the list of connective tissue diseases that are associated with TGF-beta.