The involvement of ADAMTS‐5 genetic polymorphisms in predisposition and diffusion tensor imaging alterations of lumbar disc degeneration

Abstract

Purpose: Low back pain is a global health problem in which more than 40% is caused by lumbar intervertebral disc degeneration (LDD). ADAMTS-5 (A disintegrin and metalloproteinase with thrombospondin motifs-5) was shown to be involved in LDD by functional analyses. To identify whether there is an association between ADAMTS-5 and LDD, and what is the contribution of ADAMTS-5 genetic polymorphisms to MD (Mean diffusivity) changes in lumbar IVD (Intervertebral disc). We firstly genotyped selected ADAMTS-5 SNPs (Single nucleotide polymorphisms) in a Chinese Han population. After the primary analyses of allelic, genotypic, and haplotypic association, we performed SNP-SNP interaction analysis. We subsequently genotyped another 50 participants and acquired the corresponding MD values from individual lumbar IVDs. The association analysis between the genotypic groups divided by the above positive SNPs and the corresponding MD values were also performed. Significant associations were identified in rs151058, rs229052, and rs162502. None of the 2-SNP haplotypic analysis survived the 10,000 permutation test. The following interaction analysis demonstrated that rs151058 was strong associated with LDD when conditioning on rs162502. Significant difference of MD values between AA and Gþ carriers was identified in rs162502. This is the first study indicating that the SNPs of ADAMTS-5 may contribute to predisposition of LDD. An interaction between rs151058 and rs229052 may exist in ADAMTS-5 with LDD. Keywords: lumbar disc degeneration (LDD); a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5); single nucleotide polymorphism (SNP); diffusion tensor imaging (DTI) As a global health problem, low back pain (LBP) was reported to affect about 80% of population during a lifetime.1 LBP, defined as pain radiating from the back into the dermatome of the affected nerve trunk, is a common musculoskeletal disorder characterized by symptomatic lumbar disc herniation with or without sciatica.2 More than 40% of LBP is caused by lumbar intervertebral disc degeneration (LDD). 3It was reported that about 5% of the Finnish population suffered from LDD, leading to disability in the workingage population. 4 Though several environmental and anthropometric risk factors have been showed to be related to LDD, the roles of genetic factors can never be exaggerated. 5-10The extracellular matrix (ECM), composed of collagens and proteoglycans, is crucial to normal intervertebral disc (IVD) functions.11 Previous studies indicated that the synthesis and degradation balance of ECM was interrupted by diverse matrix proteases during LDD. [12][13][14][15][16] As a large family of metalloproteases, ADAMTS-5 seems to be the most active one, 15,17,18 and has been paid increasing attentions due to their abilities in the cartilage proteoglycan cleavage. 19,20 Besides mRNA and protein of ADAMTS-5 were detected in IVDs, 21 increased levels in patients with chronic LBP and intervertebral disc herniation during LDD can be found. [22][23][24...

Autophagy: A double-edged sword in intervertebral disk degeneration

“…Trauma is also suggested as a contributor to IDD [32,33]. On the other hand, genetic contributions have been confirmed by identifying the polymorphisms of many key genes involved in the degeneration of IVD, including a disintegrin and metalloprotease with thrombospondin motif (ADAMTS)-4 [34], ADAMTS-5 [35], matrix metalloproteinase (MMP)-2 [36], MMP-3 [37], MMP-9 [38], MMP-14 [39], aggrecan [40], and vitamin D receptor [41,42]. This suggests a sophisticated interplay of multiple genetic polymorphisms in the etiology of IDD.…”

Gene Expression Profile Analysis of Human Mesenchymal Stem Cells from Herniated and Degenerated Intervertebral Discs Reveals Different Expression of Osteopontin

“…Both herniation and degeneration processes involve sequential events that lead to the loss of cellular disc matrix, and to altered biomechanics [3]. Despite growing evidence suggests that lifestyle and genetic predisposition play a role as risk factors [4], up to now the classification of herniated IVDs (H-IVDs) and degenerated IVDs (D-IVDs) is merely based on clinical observation and magnetic resonance imaging. Therefore, a better comprehension of the molecular events essential in the pathogenesis of IVD disease could represent a critical step in the development of new diagnostic tools, avoiding an ambiguous diagnosis.…”

MMPs and ADAMTSs in intervertebral disc degeneration

“…Prolonged upright posture is reported to induce AF fissures, decrease disc height and ADAMTS-5 expression, and reduce Col II and aggrecan contents in IVDs of rat cervical spine, suggesting long-term upright stance as an environmental risk factor of IDD [88,89]. Additionally, Wu et al reported that the rs2252070 SNP of ADAMTS-5 contributes to predisposition of lumbar IVD degeneration in a Chinese Han population [90]. On the other hand, application of the inhibitor of MyD88, an adapter protein that links toll-like receptors and IL-1 receptors, markedly attenuates lipopolysaccharide (LPS)-mediated induction of ADAMTS-4 and ADAMTS-5 and subsequent proteoglycan depletion in bovine NP cells [91].…”