Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes

Abstract

Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients.

Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions

“…Although we could obtain non-arthritic human SFs only from knee joints, the conservation of principal positional genes between species and diseases shows that a number of positional gene signatures in SFs are arthritis independent. Still, it can be expected that some of the site-specific differences in gene expression reflect disease-specific mechanisms in SFs that differ in different joints, as suggested recently43. We demonstrate that the transcriptional diversity of SFs translates into pronounced functional diversity, thereby creating a unique microenvironment for each joint.…”

“…Previous studies have recognized differences between hip and knee joints, mainly in the context of OA. In particular, DNA methylation patterns in chondrocytes and SFs were found to differ between these two joint locations424344. Here we study SFs from a large number of joint locations, including small joints of the hands and feet, that are characteristically and severely affected by RA.…”

Synovial tissue research: a state-of-the-art review

“…Consistent with these findings, there are differences in DNA methylation and transcriptome signatures in FLS from different joints of RA patients as well as differences in FLS invasiveness depending on their positional memory. 65,66 Questions remain about where to biopsy within a given joint. In particular there have been concerns that mediators of inflammation may be differentially expressed in different parts of the same joint, especially between the cartilage pannus junction (CPJ) and non-CPJ sites which are known to behave differently.…”

Botanicals and its extracts: Anew drug discovery and development paradigm for chronic and age-related illnesses

“…Not only is it important to identify which targets to address but it are also imperative to identify where in the pathway to intervene. In rheumatoid arthritis, the cause of inflammation in different joints was attributed to various pathways [3]. Another observation is crosstalk between rheumatoid arthritis and coronary artery disease within the same inflammation pathway [4].…”