Epigenetic differences in human cartilage between mild and severe OA

Moazedi-Fuerst, Florentine; Hofner, Manuela; Gruber, Gerald; Weinhäusel, Andreas; Stradner, Martin; Angerer, Hannes; Peischler, Daniela; Lohberger, Birgit; Glehr, Mathias; Leithner, Andreas; Sonntagbauer, Markus; Graninger, Winfried

doi:10.1002/jor.22722

Cited by 69 publications

(72 citation statements)

References 47 publications

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“…In some of these studies, differences among sample groups were most pronounced in genes involved in inflammation and immune-responses [12, 14], while others reported an over-representation of genes involved in developmental pathways [15, 16]. These studies corroborated previous findings for some identifiable genes associated with the onset and progression of OA.…”

Section: Introductionsupporting

confidence: 77%

Identification of differentially methylated regions in new genes associated with knee osteoarthritis

Bonin

Lewallen

Baheti

et al. 2016

Gene

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Epigenetic changes in articular chondrocytes are associated with osteoarthritis (OA) disease progression. Numerous studies have identified differentially methylated cytosines in OA tissues; however, the consequences of altered CpG methylation at single nucleotides on gene expression and phenotypes are difficult to predict. With the objective of detecting novel genes relevant to OA, we conducted a genome-wide assessment of differentially methylated sites (DMSs) and differentially methylated regions (DMRs). DNA was extracted from visually damaged and normal appearing, non-damaged human knee articular cartilage from the same joint and then subjected to reduced representation bisulfite sequencing. DMRs were identified using a genome-wide systematic bioinformatics approach. A sliding-window of 500bp was used for screening the genome for regions with clusters of DMSs. Gene expression levels were assessed and cell culture demethylation experiments were performed to further examine top candidate genes associated with damaged articular cartilage. More than 1,000 DMRs were detected in damaged osteoarthritic cartilage. Nineteen of these contained five or more DMSs and were located in gene promoters or first introns and exons. Gene expression assessment revealed that hypermethylated DMRs in damaged samples were more consistently associated with gene repression than hypomethylated DMRs were with gene activation. Accordingly, a demethylation agent induced expression of most hypermethylated genes in chondrocytes. Our study revealed the utility of a systematic DMR search as an alternative to focusing on single nucleotide data. In particular, this approach uncovered promising candidates for functional studies such as the hypermethylated protein-coding genes FOXP4 and SHROOM1, which appear to be linked to OA pathology in humans and warrant further investigation.

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Section: Introductionsupporting

confidence: 77%

Identification of differentially methylated regions in new genes associated with knee osteoarthritis

Bonin

Lewallen

Baheti

et al. 2016

Gene

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“…83 In another study, 1,214 differentially methylated genetic targets were identified in a comparison of paired samples of knee cartilage showing mild or severe OA. 84 A number of the identified genes were related to devel opmental and celldifferentiation pathways, supporting the proposed involvement of these mechanisms in OA. A more hypothesisdriven approach was used to demon strate that methylation of the SOX9 promoter is increased in OA, compared with normal cartilage.…”

Section: Inflammation In Oamentioning

confidence: 71%

Cartilage damage in osteoarthritis and rheumatoid arthritis—two unequal siblings

2015

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Cartilage damage is a key feature of degenerative joint disorders-primarily osteoarthritis (OA)-and chronic inflammatory joint diseases, such as rheumatoid arthritis (RA). Substantial progress has been made towards understanding the mechanisms that lead to degradation of the cartilage matrix in either condition, which ultimately results in the progressive remodelling of affected joints. The available data have shown that the molecular steps in cartilage matrix breakdown overlap in OA and RA. However, they have also, to a great extent, changed our view of the roles of cartilage in the pathogenesis of these disorders. In OA, cartilage loss occurs as part of a complex programme that resembles aspects of embryonic bone formation through endochondral ossification. In RA, early cartilage damage is a key trigger of cellular reactions in the synovium. In a proposed model of RA as a site-specific manifestation of a systemic autoimmune disorder, early cartilage damage in the context of immune activation leads to a specific cellular response within articular joints that could explain not only the organ specificity of RA, but also the chronic nature and perpetuation of the disease.

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“…Genome-wide DNA methylation studies have identified epigenomic changes in OA cartilage (54) along with differences between mild and severe OA (55), different epigenomic landscapes in hip and knee cartilage (56) and distinct clusters of OA patients (57, 58). Numerous studies have revealed the importance of DNA methylation in controlling the expression of OA-related genes, including Phlpp1 (59), IL8 (60), and genes encoding proteinases, including MMPs and ADAMTSs (28, 53, 61).…”

Section: Discussionmentioning

confidence: 99%

ELF3 modulates type II collagen gene (COL2A1) transcription in chondrocytes by inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity

Otero

Peng

Hachem

et al. 2016

Connective Tissue Research

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Aim We showed previously that ELF3 protein levels are increased in osteoarthritic (OA) cartilage, that ELF3 accounts for inflammatory cytokine-driven MMP13 gene expression, and that, upon induction by IL-1β, ELF3 binds to the COL2A1 promoter and suppresses its activity in chondrocytes. Here, we aimed to further investigate the mechanism/s by which ELF3 represses COL2A1 transcription in chondrocytes. Methods and Results We report that ELF3 inhibits Sox9-driven COL2A1 promoter activity by interfering with the activator functions of CBP/300 and Sox9. Co-transfection of the pGL2B-COL2A1 (−577/+3428 bp) reporter construct with Sox9 and with Sox5 and/or Sox6 increased COL2A1 promoter activity, and ELF3 overexpression significantly reduced the promoter transactivation. Co-transfection of ELF3 with the pLuc 4×48 enhancer construct, containing the 89-bp COL2A1 promoter and lacking the previously defined ELF3 binding sites, decreased both basal and Sox9-driven promoter activity. Co-transfection of ELF3 with a Gal4 reporter construct also inhibited Gal4-Sox9-driven transactivation, suggesting that ELF3 directly interacts with Sox9. Using truncated Sox9 fragments, we found that ELF3 interacts directly with the HMG domain of Sox9. Importantly, over-expression of ELF3 significantly decreased Sox9/CBP-dependent HAT activity. Finally, we show evidence that increased ELF3 mRNA expression in OA chondrocytes correlates with hypermethylation of the proximal promoter, suggesting that ELF3 transcription is subjected to epigenetic control in OA disease. Conclusion Our results highlight the contribution of ELF3 to transcriptional regulation of COL2A1 and its potential role in OA disease, and uncover epigenetic mechanisms at play in the regulation of ELF3 and its downstream targets in articular chondrocytes.

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Epigenetic differences in human cartilage between mild and severe OA

Cited by 69 publications

References 47 publications

Identification of differentially methylated regions in new genes associated with knee osteoarthritis

Identification of differentially methylated regions in new genes associated with knee osteoarthritis

Cartilage damage in osteoarthritis and rheumatoid arthritis—two unequal siblings

ELF3 modulates type II collagen gene (COL2A1) transcription in chondrocytes by inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity

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