A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease.
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.
Seki
Shoji
S
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.
Kawaguchi
Yoshiharu
Y
Chiba
Kazuhiro
K
Mikami
Yasuo
Y
Kizawa
Hideki
H
Oya
Takeshi
T
Mio
Futoshi
F
Mori
Masaki
M
Miyamoto
Yoshinari
Y
Masuda
Ikuko
I
Tsunoda
Tatsuhiko
T
Kamata
Michihiro
M
Kubo
Toshikazu
T
Toyama
Yoshiaki
Y
Kimura
Tomoatsu
T
Nakamura
Yusuke
Y
Ikegawa
Shiro
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D004198:Disease Susceptibility; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007405:Intervertebral Disc Displacement / Q000235:genetics*; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; C114607:CILP protein, human; D011755:Pyrophosphatases