A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease

Abstract

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.

Association between the -1306C/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults

“…Several studies have found familial predisposition to LDD, including early onset sciatica and lumbar disc herniation. In addition, mutations or polymorphisms in several genes have been reported to be associated with either the presence or severity of disc degeneration, including gene coding for collagen IX and XI [2,12,13], aggrecan [9], cartilage intermediate layer protein [18], vitamin D receptor [22], interleukin-1 [19], matrix metalloproteinase-3(MMP-3) [20], tissue inhibitor of metalloproteinase-1(TIMP-1) [21], and cyclooxygenase-2 [21].…”

What is Intervertebral Disc Degeneration, and What Causes It?

“…1 Individual genes associated with disc degeneration include those for collagen type IX, 91 aggrecan, 92 vitamin D receptor, 93 MMP3, 94 and cartilage intermediate layer protein. 95 The products of these genes probably affect the strength of skeletal tissues, and their systemic effects may explain why disc degeneration is more prevalent in those with osteoarthritis. 74 Environmental risk factors for disc degeneration include high and repetitive mechanical loading 1,96 and smoking cigarettes.…”

Cartilage Intermediate Layer Protein 2 (CILP-2) Is Expressed in Articular and Meniscal Cartilage and Down-regulated in Experimental Osteoarthritis

“…CILP was originally isolated from human articular cartilage, is a large secreted glycoprotein, and is thought to play a role in cartilage scaffolding (6). CILP has been associated with osteoarthritis (12)(13)(14), and more recently with lumbar disc disease in a Japanese population (8), and will be referred to hereafter as CILP1 (5). We and others have shown CILP-1 and CILP-2 to be structurally similar (5) (supplemental Fig.…”

“…CILP-1 levels have been shown to increase with age (6,10) and in patients with early stage osteoarthritis (11). The association of single nucleotide polymorphisms in the CILP1 gene with musculoskeletal disorders including osteoarthritis (12)(13)(14), and lumbar disc disease in a Japanese population (8) implies that CILP proteins may be important in cartilage structure and disease. In contrast to CILP-1, little is known about the mRNA and protein expression of CILP-2 in cartilage and noncartilaginous tissues.…”

“…CILP-1 is a pro-form of two polypeptides, and is cleaved into distinct N-and C-terminal fragments at a furin endoprotease consensus site (7). The N-terminal of CILP-1 has been shown to bind to and inhibit TGF␤1 in vitro (8), and CILP1 mRNA is induced by TGF␤1 (9). CILP-1 levels have been shown to increase with age (6,10) and in patients with early stage osteoarthritis (11).…”