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Lumbar-disc herniation (LDH), one of the most common musculoskeletal diseases, has strong genetic determinants. Recently, several genes that encode extracellular matrix (ECM) proteins in the intervertebral disc have been reported to associate with LDH. Thrombospondins (THBSs) 1 and 2 are good candidates for the LDI-I susceptibility gene: They are intervertebral disc ECM proteins that regulate the effective levels of matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling. Here, we report that THBS2 is associated with LDH in Japanese populations. An intronic SNP in THBS2 (IVS10-8C → T; rs9406328) showed significant association (p = 0.0000028) with LDH in two independent Japanese populations. This SNP, located in a polypyrimidine tract upstream of the 3' splice site of intron 10, exerts allelic differences on exon 11 skipping rates in vivo, with the susceptibility allele showing increased skipping. Skipping of exon 11 results in decreased THBS2 interaction with MMP2 and MMP9. Further, a missense SNP in MMP9 (Q279R; rs17576) is also strongly associated with LDH in the Japanese population (p = 0.00049) and shows a combinatorial effect with THBS2 (odds ratio 3.03, 95% confidence interval 1.58-5.77). Thus, a splicing-affecting SNP in THBS2 and a missense SNP in MMP9 are associated with susceptibility to LDH. Our data indicate that regulation of intervertebral disc ECM metabolism by the THBS2MMP system plays an essential role in the etiology and pathogenesis of LDH. [ABSTRACT FROM AUTHOR]

Lumbar disc herniation (LDH), degeneration and herniation of the nucleus pulposus of the intervertebral disc (IVD) of the lumbar spine, is one of the most common musculoskeletal diseases. Its etiology and pathogenesis, however, remain unclear. Type XI collagen is important for cartilage collagen formation and for organization of the extracellular matrix. We identified an association between one of the type XI collagen genes, COL11A1, and LDH in Japanese populations. COL11A1, which encodes the a1 chain of type XI collagen, was highly expressed in IVD, but its expression was decreased in the IVD of patients with LDH. The expression level was inversely correlated with the severity of disc degeneration. A single-nucleotide polymorphism (c.4603C→T [rs1676486]) had the most significant association with LDH (P = 3.3 x 10-6), and the transcript containing the disease-associated allele was decreased because of its decreased stability. These observations indicate that type XI collagen is critical for IVD metabolism and that its decrease is related to LDH. [ABSTRACT FROM AUTHOR]