PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS

Abstract

Rheumatoid arthritis is a synovial inflammatory disease marked by joint infiltration by immune cells and damage to the extracellular matrix. Although genetics plays a critical role in heritability and its pathogenesis, the relative lack of disease concordance in identical twins suggests that noncoding influences can affect risk and severity. Environmental stress, which can be reflected in the genome as altered epigenetic marks, also contributes to gene regulation and contributes to disease mechanisms. Studies on DNA methylation suggest that synovial cells, most notably fibroblast-like synoviocytes, are imprinted in rheumatoid arthritis with epigenetic marks and subsequently assume an aggressive phenotype. Even more interesting, the synoviocyte marks are not only disease specific but can vary depending on the joint of origin. Understanding the epigenetic landscape using unbiased methods can potentially identify nonobvious pathways and genes that that are responsible for synovial inflammation as well as the diversity of responses to targeted agents. The information can also be leveraged to identify novel therapeutic approaches.

Fig. 1

Hierarchical clustering of methylomes. Late rheumatoid arthritis (RA) and osteoarthritis (OA) segregate based on their methylation patterns. Early RA (ERA) and juvenile idiopathic arthritis (JIA) forms separate subgroups within RA. Reprinted from Ai et al. (11).

Fig. 2

Principle component analysis (PCA) of hip and knee methylomes in rheumatoid arthritis (RA). DNA methylation in fibroblast-like synoviocytes (FLS) isolated from RA hips and knees showed distinct methylation patterns. The PCA shows differentially methylated loci that distinguish RA hip and knee FLS Reprinted from Ai et al. (15).