The Role of Epigenetic Mechanism in Pathogenesis of the Osteoarthritis

Abstract

Osteoarthritis is a multifactorial disease characterized by the degeneration of articulating synovial joints. Osteoarthritis is more prevalent in women. It caused by ageing, pathophysiological situations, ecological factors, hormonal, environmental, and genetic factors. Epigenetic is “in addition to genetics. Epigenetic mechanisms such as histone modifications, DNA methylation and non-coding RNA are important parameters in controlling quantity, location and timing of gene expression. The treatment available is only painkillers and anti-inflammatory. In this review, we discuss how these epigenetic mechanisms are involved in the pathogenesis of osteoarthritis and find possible therapeutic targets in the prevention of disease. Epigenetic mechanisms regulate gene expression either by disturbing gene transcription or by acting post-transcription. In mammals DNA methylation is occur at Cp G dinucleotides at the outside of CpG. However cytosine is specifically methylated to 5-methylcytosine, later it can be transformed to 5-hydroxymethylcytosine that plays a role in epigenetics. DNA methylation is mediated by DNA methyl-transferases (DNMT1,-3a, -3b). DNA methylation occur at CpGdinucleotides that clustered close to gene promoters and caused suppression of genes expression. Methylation modifications on promoter regions of these genes (MMP3, MMP9, MMP13 and ADAMTS-4) have been reported. In the promoter site of such enzymes the entire proportion of non-methylated sites in OA cartilage is increased. Histone modifications modify the chromatin assembly. Histone modifications include acetylation, phosphorylation, methylation and ubiquitination. Histone acetylation and deacetylation play a role in the pathophysiology of OA by disturbing chondrocyte anabolic and catabolic processes. Histone acetylation is modulated by histone acetyltransferases (HATs) and deacetylation by histone deacetylases. HDACs (HDAC1, HDAC2, and HDAC7) increase cartilage demolition. microRNAs (miRNAs) are single stranded RNA. miRNAs involved in the pathogenesis of OA. After binding to target sequence, miRNAs silence genes either by cleavage of their respective target mRNA or by preventing gene translation. Many miRNA (miR-140, miR-9 etc) and some other RNAs such as piRNAs, snoRNAs and lncRNAs have role in OA progression. The deletion of a single miRNA, miR-140, has a clear developmental phenotype with an early onset OA. To date, epigenetic functions of lncRNAs in response to inflammation and in potentially regulating chondrocyte homeostasis are completely unknown.