Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs

Abstract

Osteoarthritis (OA) is a complex multifactorial disease with a strong genetic component. Several studies have suggested or identified epigenetic events that may play a role in OA progression and the gene expression changes observed in diseased cartilage. The aim of this review is to inform about current research in epigenetics and epigenetics in OA. Epigenetic mechanisms include DNA methylation, histone modifications, and microRNAs. Collectively, these enable the cell to respond quickly to environmental changes and can be inherited during cell division. However, aberrant epigenetic modifications are associated with a number of pathological conditions, including OA. Advancements in epigenetic research suggests that global analysis of such modifications in OA are now possible, however, with the exception of microRNAs, it will be a significant challenge to demonstrate how such events impact on the disease.

DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism

“…The OA loci discovered to date explain only a small fraction of the heritability of OA estimated by epidemiological studies. It is now becoming clear that some of the missing heritability may be explained by inheritance of epigenetic modifications of genomic DNA (16)(17)(18).…”

Regulated Transcription of Human Matrix Metalloproteinase 13 (MMP13) and Interleukin-1β (IL1B) Genes in Chondrocytes Depends on Methylation of Specific Proximal Promoter CpG Sites

“…Moreover, only a few reports have addressed how methylation of individual CpG sites influences the promoter activity of a specific gene (6,10,11), and the relative contributions of the methylation status of each individual CpG site to the transcriptional regulation of a given gene in vivo remain largely unexplored. In addition, although epigenetic gene regulation has been broadly investigated in other contexts, little is known about the specific impact of this mechanism of gene control in musculoskeletal diseases (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

The first international workshop on the epigenetics of osteoarthritis

“…There are three known mechanisms of epigenetic gene regulation: DNA methylation, histone modifications, and noncoding regulatory RNAs. The first two mechanisms regulate gene expression by modulating gene transcription, whereas regulatory RNAs act post-transcriptionally (13). Epigenetic patterns are both plastic, especially during development and cell differentiation when they undergo dynamic changes, and stable, allowing cellular identity to be maintained during mitotic cell division.…”

“…Deletion of miR-140 in mice causes a shorter skeleton and earlyonset OA (65). MicroRNAs are transcribed as a stemloop transcript with a -5p and -3p microRNA, either or both of which can be functional after processing (13). Because the miR-140 null mouse lacks both miR-140-5p and miR-140-3p, it is unclear which is most active in cartilage.…”