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Genome-wide DNA methylation profile analysis of human intervertebral disc degeneration

ABSTRACT: The pathophysiology of intervertebral disc (IVD) degeneration is not entirely understood; however, environmental and endogenous factors under genetic predisposition are considered to initiate the degenerative changes of human IVDs. Aberrant epigenetic alterations play a pivotal role in several diseases, including osteoarthritis. However, epigenetic alternations, including DNA methylation, in IVD degeneration have not been evaluated. The purpose of this study was to comprehensively compare the genome-wide DNA methylation profiles of human IVD tissues, specifically nucleus pulpous (NP) tissues, with early and advanced stages of disc degeneration. We conducted, for the first time, a genome-wide DNA methylation profile comparative study and observed significant differences in DNA methylation profiles between early and advanced stages of human IVD degeneration. The overview of the DNA methylation profile in the current study revealed that differentially methylated loci were identified in many genes associated with known molecules that have been reported to be relevant to IVD degeneration. Importantly, changes in DNA methylation profiles were also found in genes that regulate the major signaling pathways, such as NF-κB, MAPK, and Wnt signaling, that are well known to be responsible for the pathogenesis of human disc degeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129789 | GEO | 2019/10/01

REPOSITORIES: GEO

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Project description:Objective: Aging and early degeneration of the intervertebral disc (IVD) involves the substition of notochordal cells (NCs) in the nucleus pulposus (NP) by chondrocyte-like cells (CLCs). This study investigated the gene expression profiles involved in this process using NP tissue from both non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occuring IVD degeneration. Methods: Dual channel DNA microarrays were used to compare 1) healthy NP tissue, 2) NP tissue with a mixed population of NCs and CLCs, and 3) NP tissue containing solely CLCs. Canonical Wnt-signaling was validated using qPCR of relevant Wnt target genes. Caveolin-1, a known regulator of canonical Wnt signaling, was investigated further in tissue sections using qPCR and immunohistochemistry, and in cultured NCs by qPCR and immunofluorescence. Also, the NP of 3-month-old caveolin-1 knock-out mice was histopathologically evaluated and compared with wild type mice of the same age. Results: Early IVD degeneration involved significant regulations in numerous pathways, such as extracellular matrix remodeling, Bone Morphogenetic Protein- , and Wnt/beta-catenin-signaling. With regard to Wnt/beta-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant downregulation of axin2 gene expression and caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of 3-month-old WT mice were rich in viable NCs, whereas the NPs of 3-month-old caveolin-1 knock-out mice contained chondroid-like matrix with small, rounded cells, the majority of which showed morphological signs of apoptosis. Conclusions: Aging and the onset of degeneration of the IVD involve significant downregulation of canonical Wnt signaling and caveolin-1, which appears to be essential in the physiology and preservation of NCs. DNA microarrays were used to compare nucleus palposus (NP) tissue of healthy and chondrodystrophic individuals. Furthermore, the situation of the tissue was divided into three stages: NCR: notochordal cell(NC) rich; CR: tissue containing solely chondrocyte-like-cells (CLC) and T: tissue with a mixed population of NCs and CLCs. Comparisons were analysed on a 2-color platform against a common reference sample, consisting of a multitude of canine organs, including liver, spleen, kidney, lung, hart, intestine and bone.

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Genome-wide DNA methylation profile analysis of human intervertebral disc degeneration

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