Epigenetic modifications of interleukin-6 in synovial fibroblasts from osteoarthritis patients

Fei Yang,Yan Huang,Zhenan Zhu,Chuandong Wang,Mengning Yan,Jian Tang,Song Zhou,Huiwu Li,You Wang

doi:10.1038/srep43592

Abstract

Osteoarthritis (OA) is the most common degenerative disease of the synovial joint. The synovial membrane is responsible for the inflammatory reaction leading to the secretion of macrophage-derived pro-inflammatory cytokines, such as IL-6. Suppressing IL-6 over-expression in synovial fibroblasts (SF) is a promising method to prevent OA development and progression, in which the prerequisite is the elucidation of the molecular mechanisms underlying IL-6 over-expression in SF. Currently, there are few reports concerning epigenetic modifications in IL-6 in OA SF. In the present study, we attempted to investigate this phenomenon. SF over-expressing IL-6 was collected from OA patients. DNA hypomethylation and histone hyperacetylation were observed in the IL-6 promoter regions in OA SF compared with normal SF. No differences in the status of H3K9 di-methylation, H3K27 tri-methylation and H3K4 tri-methylation were observed in the IL-6 promoter regions between normal and OA SF. DNA (cytosine-5-)-methyltransferase 3 alpha (Dnmt3a) overexpression and anacardic acid (histone acetyltransferase inhibitor) treatment increased DNA methylation and decreased histone acetylation in the IL-6 promoter, and IL-6 over-expression in OA SF was suppressed. These observations provide deeper insight into the pathogenesis of OA and can be used to design new drugs and develop new therapeutic methods to treat OA.

Highlights

Osteoarthritis (OA) is the most prevalent degenerative disease affecting synovial joint
The results revealed the significant upregulation of IL-6 mRNA in OA synovial fibroblasts (SF) compared with normal controls (Fig. 1A)
The results revealed higher IL-6 levels in synovial fluid from OA patients compared with normal controls (Fig. 1D)

Summary

Introduction

Osteoarthritis (OA) is the most prevalent degenerative disease affecting synovial joint. The precise etiology of OA remains unknown[3], the consensus has been built that the synovial membrane plays an important role in the joint chronic inflammation, neovascularization and cartilage destruction in which macrophage-derived pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8 and TNF-α, are involved[4,5,6]. In addition to DNA methylation, histone modifications play an essential role in gene transcription. They include methylation, acetylation, phosphorylation, SUMOylation and ubiquitination so on. These histone modifications regulate gene transcription through www.nature.com/scientificreports/. Among the various forms of histone modifications, acetylation is generally associated with gene transcription activation, whereas the role of methylation depends on the site and number of methyl groups (i.e., mono-, di- or tri-methylation). Under OA pathogenic conditions, the promoter of Sox[9] was observed to have elevated levels of trimethylation of H3K9 and H3K27, and decreased acetylation of H3K9, 15, 18, 23, and 27, which collectively leads to transcriptional repression of Sox[914]

Methods

Results

Conclusion