Joint-specific differences in epigenetic imprinting and gene expression suggest that disease mechanisms in rheumatoid arthritis (RA) may vary from joint to joint, which may possibly explain some of the varying drug responses among patients with RA, researchers have found.
“Previous studies suggest that pathogenesis of RA is similar in all affected joints,” noted Rizi Ai, PhD, Postdoctoral Scholar, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, and colleagues. “Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis (OA) FLS, but also distinguish RA FLS isolated from knees and hips.”
With the understanding that stratifying patients based on their molecular signatures could assist with developing therapies that target pathways specific to a particular disease or tissue location, and in response to their hypothesis that epigenetic patterns in FLS contribute to differences in synovial inflammation and clinical response, the investigators conducted a study examining the epigenetic patterns in joint cells of patients with RA and OA.
“We focused on FLS for a variety of reasons, most notably because they display a unique aggressive phenotype in RA and contribute to cytokine production and joint damage,” the investigators explained. “They also have not been targeted by new therapeutics and are a treatment opportunity that would not affect adaptive immunity.”
Among the full joint cell data set from patients with RA (n = 30) and OA (n = 16), Dr Ai and colleagues identified 13,577 differentially methylated loci, 1714 differentially methylated genes, and 67 meaningfully enriched pathways (44 of which overlapped with previous data, especially in pathways that involved inflammation and immune responses).
They then looked to determine the joint-specific DNA methylation signatures in RA hip and knee FLS and OA knee and hip joints; identify joint-specific biological pathways and potential therapeutic implications; biologically validate joint-specific FLS function; compare RA knee and hip differences to RA/OA differences; and define disease-specific differences in knees and hips.
The results demonstrated that RA FLS have distinct DNA methylation and gene-expression patterns that are dependent on the joint of origin, leading the investigators to postulate that joints may respond differentially to highly targeted therapeutic agents, and that this likelihood should be considered during the development of clinical trials.
“As expected, within-disease changes (for example, RA hip to RA knee) were less than the differences between RA and OA,” stated Dr Ai and colleagues. “Pathways and genes that are most likely related to hip and knee development because they were shared across diseases were estimated and subtracted from the RA hip and knee data to estimate RA-specific changes. The RA hip- or knee-specific pathways are related to inflammation and immune responses and support the notion that RA joints could have distinct pathogenic mechanisms.”
Although some of the joint-specific differences found in epigenetic imprinting and gene expression could be attributed to the role of FLS in joint development, the study authors note the evidence of differential gene-expression and methylation pathways specific to RA.
They conclude that the disparities between methylome and transcriptome in knees and hips in patients with RA may possibly contribute to the diverse responses to highly targeted agents by different patients.
- Ai R, Hammaker D, Boyle DL, et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun. 2016;7:11849.