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Intervertebral disc development and disease-related genetic polymorphisms.

ABSTRACT: The intervertebral disc (IVD) comprises a gelatinous inner core (nucleus pulposus; NP) and concentric rings (annulus fibrosus; AF). The NP, an important structure for shock absorption in the vertebrate spinal motion segment, can be traced back to the notochord in ontogenetic lineage. In vertebrates, the notochord undergoes mucinoid changes, and had been considered vestigial until recently. However, observed correlations between IVD degeneration and back pain in humans have renewed interest in the IVD in biomedical fields. Beyond its mechanical contribution to development, the notochord is also an essential signaling center, which coordinates formation of the neural tube and somites. The pertinent signaling molecules, particularly TGF-? and bone morphogenetic proteins (BMPs), continue to play roles in the adult tissues and have been utilized for tissue regeneration. Genetic factors are major determinants of who will develop IVD degeneration and related back pain, and seem to correlate better with disc degeneration and back pain than do external forces on the spine. In summary, the spinal column is a landmark development in evolution. Genes directing the development of the IVD may also contribute to its maintenance, degeneration, and regeneration. Likewise, structural genes as well as genes responsible for maintenance of the structure are related to IVD degeneration. Finally, genes responsible for inflammation may play a dual role in exacerbating degeneration or facilitating repair responses depending on the context.

SUBMITTER: Ashley JW

PROVIDER: S-EPMC6150108 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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Intervertebral disc development and disease-related genetic polymorphisms.

Ashley Jason W JW Enomoto-Iwamoto Motomi M Smith Lachlan J LJ Mauck Robert L RL Chan Danny D Lee Joseph J Heyworth Martin F MF An Howard H Zhang Yejia Y

Genes & diseases 20160423 3

The intervertebral disc (IVD) comprises a gelatinous inner core (nucleus pulposus; NP) and concentric rings (annulus fibrosus; AF). The NP, an important structure for shock absorption in the vertebrate spinal motion segment, can be traced back to the notochord in ontogenetic lineage. In vertebrates, the notochord undergoes mucinoid changes, and had been considered vestigial until recently. However, observed correlations between IVD degeneration and back pain in humans have renewed interest in th ...[more]

PMID: 30258887

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Project description:Background contextDisc degeneration (DD) is a multifaceted chronic process that alters the structure and function of the intervertebral discs and can lead to painful conditions. The pathophysiology of degeneration is not well understood, but previous studies suggest that certain genetic polymorphisms may be important contributing factors leading to an increased risk of DD.PurposeTo review the genetic factors in DD with a focus on polymorphisms and their putative role in the pathophysiology of degeneration. Elucidating the genetic components that are associated with degeneration could provide insights into the mechanism of the process. Furthermore, defining these relationships and eventually using them in a clinical setting may allow an identification and early intervention for those who are at a high risk for painful DD.Study designLiterature review.MethodsThis literature review focused on the studies concerning genetic polymorphisms and their associations with DD.ResultsGenetic polymorphisms in 20 genes have been analyzed in association with DD, including vitamin D receptor, growth differentiation factor 5 (GDF5), aggrecan, collagen Types I, IX, and XI, fibronectin, hyaluronan and proteoglycan link protein 1 (HAPLN1), thrombospondin, cartilage intermediate layer protein (CILP), asporin, MMP1, 2, and 3, parkinson protein 2, E3 ubiquitin protein ligase (PARK2), proteosome subunit ? type 9 (PSMB9), tissue inhibitor of metalloproteinase (TIMP), cyclooxygenase-2 (COX2), and IL1?, IL1?, and IL6. Each genetic polymorphism codes for a protein that has a functional role in the pathogenesis of DD.ConclusionsThere are known associations between several genetic polymorphisms and DD. Of the 20 genes analyzed, polymorphisms in vitamin D receptor, aggrecan, Type IX collagen, asporin, MMP3, IL1, and IL6 show the most promise as functional variants. Genetic studies are crucial for understanding the mechanism of the degeneration. This genetic information could eventually be used as a predictive model for determining a patient's risk for symptomatic DD.

Project description:BackgroundIntervertebral disc degeneration (IVDD) is considered a multifactorial disease that is influenced by both environmental and genetic factors. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single-nucleotide polymorphisms (SNPs) that are associated with IVDD.AimThis review presents comprehensive and updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD. An organized collection of information is provided regarding genetic polymorphisms that have been identified to influence the risk of developing IVDD. Understanding the proteins and signaling systems involved in IVDD can lead to improved understanding and targeting of therapeutics.Materials and methodsAn electronic literature search was performed using the National Library of Medicine for publications using the keywords genetics of IVDD, lumbar disc degeneration, degenerative disc disease, polymorphisms, SNPs, and disc disease. The articles were then screened based on inclusion criteria that included topics that covered the correlation of SNPs with developing IVDD. Sixty-five articles were identified as containing relevant information. Articles were excluded if they investigated lower back pain or just disc herniation without an analysis of disc degeneration. This study focuses on the chronic degeneration of IVDs.ResultsVarious genes were identified to contain SNPs that influenced the risk of developing IVDD. Among these are genes contributing to structural proteins, such as COL1A1, COL9A3, COL9A3, COL11A1, and COL11A2, ACAN, and CHST3. Furthermore, various SNPs found in the vitamin-D receptor gene are also associated with IVDD. SNPs related to inflammatory cytokine imbalance are associated with IVDD, although some effects are limited by sex and certain populations. SNPs in genes that code for extracellular matrix-degrading enzymes, such as MMP-1, MMP-2, MMP-3, MMP-9, MMP-14, ADAMTS-4, and ADAMTS-5 are also associated with IVDD. Apoptosis-mediating genes, such as caspase 9 gene (CASP9), TRAIL, and death receptor 4 (DR4), as well as those for growth factors, such as growth differentiation factor 5 and VEGF, are identified to have polymorphisms that influence the risk of developing IVDD.ConclusionWithin the last 10 years, countless new SNPs have been identified in genes previously unknown to be associated with IVDD. Furthermore, the last decade has also revealed new SNPs identified in genes already known to be involved with increased risk of developing IVDD. Improved understanding of the numerous genetic variants behind various pathophysiological elements of IVDD could help advance personalized care and pharmacotherapeutic strategies for patients suffering from IVDD in the future.

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Intervertebral disc development and disease-related genetic polymorphisms.

Publications

Intervertebral disc development and disease-related genetic polymorphisms.

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