Seki Shoji, Kawaguchi Yoshiharu, Chiba Kazuhiro, Mikami Yasuo, Kizawa Hideki, Oya Takeshi, Mio Futoshi, Mori Masaki, Miyamoto Yoshinari, Masuda Ikuko, Tsunoda Tatsuhiko, Kamata Michihiro, Kubo Toshikazu, Toyama Yoshiaki, Kimura Tomoatsu, Nakamura Yusuke, Ikegawa Shiro
Laboratory for Bone and Joint Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Nat Genet. 2005 Jun;37(6):607-12. doi: 10.1038/ng1557. Epub 2005 May 1.
Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, LDD has strong genetic determinants. 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-beta1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-beta1-mediated induction of cartilage matrix genes through direct interaction with TGF-beta1 and inhibition of TGF-beta1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-beta1. 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.
腰椎间盘疾病（LDD）是由腰椎间盘退变引起的。作为最常见的肌肉骨骼疾病之一，LDD具有很强的遗传决定因素。通过病例对照关联研究，我们在编码软骨中间层蛋白的CILP中鉴定出一个功能性单核苷酸多态性（1184T→C，导致氨基酸替换I395T），它是LDD易感性的调节因子。CILP在椎间盘中大量表达，并且随着椎间盘退变的进展其表达增加。在椎间盘中，CILP与TGF-β₁在聚集的软骨细胞及其区域基质中共定位。CILP通过与TGF-β₁直接相互作用并抑制TGF-β₁信号传导，抑制TGF-β₁介导的软骨基质基因诱导。与易感性相关的1184C等位基因显示出对TGF-β₁的结合和抑制增加。因此，我们得出结论，细胞外基质蛋白CILP调节TGF-β信号传导，并且这种调节在LDD的病因学和发病机制中起关键作用。我们的研究还增加了与TGF-β相关的结缔组织疾病的种类。
