Transcriptional Associations of Osteoarthritis‐Mediated Loss of Epigenetic Control in Articular Cartilage

Abstract

Objective. To identify osteoarthritis (OA) progressionmodulating pathways in articular cartilage and their respective regulatory epigenetic and genetic determinants in end-stage disease.Methods. Transcriptional activity of CpG was assessed using gene expression data and DNA methylation data for preserved and lesional articular cartilage samples. Disease-responsive transcriptionally active CpG were identified by means of differential methylation between preserved and lesional cartilage. Transcriptionally relevant genetic determinants were addressed by means of single-nucleotide polymorphisms (SNPs) proximal to the OA-responsive transcriptionally active CpG. Statistical analyses were corrected for age, sex, joint, and technical covariates. A random effect was included to correct for possible correlations between paired samples.Results. Of 9,838 transcribed genes in articular cartilage, 2,324 correlated with the methylation status of 3,748 transcriptionally active CpG; both negative (n 5 1,741) and positive (n 5 2,007) correlations were observed. Hypomethylation and hypermethylation (false discovery rate of <0.05, |Db| > 0.05) were observed for 62 and 25 transcriptionally active CpG, respectively, covering 70 unique genes. Enrichment for developmental and extracellular matrix maintenance pathways indicated possible reactivation of endochondral ossification. Finally, we observed 31 and 26 genes for which methylation and expression, respectively, were additionally affected by genetic variation.Conclusion. We identified tissue-specific genes involved in OA disease progression, reflected by genetic and pathologic epigenetic regulation of transcription, primarily at genes involved in development. Therefore, transcriptionally active SNPs near these genes may serve as putative susceptibility alleles. Our results constitute an important step toward understanding the reported widespread epigenetic changes occurring in OA articular cartilage and toward subsequent development of treatments targeting disease-driving pathways.Osteoarthritis (OA) is the most prevalent arthritis among the elderly (1) and is currently recognized as a disease of the whole joint (2). A well-described hallmark of OA is articular cartilage degradation (3). The single cell type present in articular cartilage is the articular chondrocyte, which is a highly specialized, maturation-arrested, nonproliferating cell. To ensure articular cartilage integrity throughout life, the articular chondrocyte needs to adapt its behavior in response to external signals, such as mechanical stress, aging, or microtraumas (4). To facilitate

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

“…Array-based surveys have revealed significant differences in DNA methylation between OA and non-OA bone and cartilage in the human hip and knee at hundreds to thousands of CpG sites throughout the genome [11–16]. 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].…”

Chondroprotective effects of the combination chondroitin sulfate-glucosamine in a model of osteoarthritis induced by anterior cruciate ligament transection in ovariectomised rats

“…OA is the most prevalent joint condition and a leading cause of disability in the world [2]. In the last years, major efforts have been made to identify genetic and epigenetic mechanisms involved in the development of OA [3] as well as the role of ageing, obesity, joint injury, biomechanical stress, inflammation, hormone levels, metabolic disease, etc. [4,5].…”

The first international workshop on the epigenetics of osteoarthritis

“…The advent of high-throughput CpG DNA methylation arrays has enabled investigators to directly compare, at a genome-wide level, OA and non-OA methylomes and to compare methylation status between DNA from different sites within the joint and between different joints (17)(18)(19)(20)(21)(22). These arrays have also been used to assess whether there are direct links between OA genetic risk loci and epigenetic status, and between gene expression and epigenetics (23,24).…”

“…Together, these studies demonstrated OA risk alleles that confer susceptibility to OA via changing the epigenetically modulated gene expression. Nonetheless, genomewide analysis of the transcriptome and methylome of articular cartilage revealed that only 24% of the differentially methylated CpG sites correlated to proximal in cis gene expression and as such could be considered transcriptionally active in articular cartilage (19,24). Moreover, it was shown that for 31 and 26 OA cartilage-relevant genes, methylation and expression, respectively, are additionally affected by genetic variation proximal to these genes, which may further modify the OA pathophysiology (19,24).…”