NEW YORK (Reuters Health) - A mutation in the gene encoding cartilage intermediate layer protein (CILP) inhibits transforming growth factor (TGF)-beta-1 in chondrocytes of the intervertebral disc, leading to lumbar disc disease, according to a report in Nature Genetics published online on May 1st.
Lumbar disc disease has a strong familial predisposition, suggesting that genetic factors are important in its etiology, senior author Dr. Shiro Ikegawa of the Institute of Physical and Chemical Research, Tokyo and associates point out.
To investigate genes that might be involved, they genotyped candidate genes from 188 cases and 376 controls and identified three single nucleotide polymorphisms (SNPs) that might be implicated. Further analysis in another group of 279 cases and 278 controls showed a significant association between one particular SNP in CILP and lumbar disc disease. The SNP resulted in a threonine-isoleucine substitution at codon 395 (I395T).
In their analysis of various human tissues and cells, the team detected CILP in intervertebral disc tissue, with CILP mRNA expression increasing among individuals with disc degeneration.
In the absence of full-length CILP, TGF-beta-1 induced expression of aggrecan and type II collagen in disc tissue. Binding to TGF-beta-1 was increased and induction of the proteins was inhibited in the presence of full-length CILP, say the investigators, and the inhibition was further increased in CILP with the threonine substitution.
“The aberrantly increased inhibitory effects of CILP attributed to the susceptible allele would perturb the balance of TGF-beta control over chondrocyte metabolism and intervertebral disc tissue maintenance,” the researchers suggest, “leading to susceptibility to lumbar disc disease caused by inadequate response of intervertebral disc cells to injury and mechanical stress.”
They add that agents to control and modify the TGF-beta-extracellular matrix system “are promising targets for treatment, presenting a new therapeutic strategy for lumbar disc disease.”
Source: Nat Genet 2005. [ Google search on this article ]
MeSH Headings:Scleroproteins: Transforming Growth Factors: Transforming Growth Factor beta: Extracellular Matrix Proteins: Polymorphism, Single NucleotideCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
