Epigenetic Regulation of Nutrient Transporters in Rheumatoid Arthritis Fibroblast‐like Synoviocytes

Abstract

Objective Since previous studies indicate that metabolism is altered in rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS), we undertook this study to determine if changes in the genome‐wide chromatin and DNA states in genes associated with nutrient transporters could help to identify activated metabolic pathways in RA FLS. Methods Data from a previous comprehensive epigenomic study in FLS were analyzed to identify differences in genome‐wide states and gene transcription between RA and osteoarthritis. We utilized the single nearest genes to regions of interest for pathway analyses. Homer promoter analysis was used to identify enriched motifs for transcription factors. The role of solute carrier transporters and glutamine metabolism dependence in RA FLS was determined by small interfacing RNA knockdown, functional assays, and incubation with CB‐839, a glutaminase inhibitor. We performed 1H nuclear magnetic resonance to quantify metabolites. Results The unbiased pathway analysis demonstrated that solute carrier–mediated transmembrane transport was one pathway associated with differences in at least 4 genome‐wide states or gene transcription. Thirty‐four transporters of amino acids and other nutrients were associated with a change in at least 4 epigenetic marks. Functional assays revealed that solute carrier family 4 member 4 (SLC4A4) was critical for invasion, and glutamine was sufficient as an alternate source of energy to glucose. Experiments with CB‐839 demonstrated decreased RA FLS invasion and proliferation. Finally, we found enrichment of motifs for c‐Myc in several nutrient transporters. Conclusion Our findings demonstrate that changes in the epigenetic landscape of genes are related to nutrient transporters, and metabolic pathways can be used to identify RA‐specific targets, including critical solute carrier transporters, enzymes, and transcription factors, to develop novel therapeutic agents.

A Smart Nanoreactor Based on an O2-Economized Dual Energy Inhibition Strategy Armed with Dual Multi-stimuli-Responsive “Doorkeepers” for Enhanced CDT/PTT of Rheumatoid Arthritis

“…Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis, progressive articular cartilage erosion, and bone destruction, which is regulated by a complex pathological process involving multiple inflammatory cells. , Nowadays, pathological research has revealed that fibroblast-like synovial (FLS) cells are one of the critical effector cells in RA, and their hyperproliferation and infiltration play a key role in the pathogenesis of RA. , Once RA happens, the two- to three-layer synovial lining would be converted to rheumatoid and pannus-like, which is a hyperplastic structure with a greater amount of stimulated FLS cells and macrophages that stretches into the articular interior, connects to the cartilage surface, and infiltrates and decomposes the cartilage matrix leading to bone loss and joint dysfunction. − Recently, many research reports demonstrate that the activation of FLS cells and subsequent joint injury are closely related to the changes of intracellular energy metabolism. , In RA activated FLS (RA-FLS) cells, the balance of the glucose metabolism is disturbed, which is reflected as the proportion of the glycolysis pathway being obviously higher than that of the oxidative phosphorylation pathway. With the rise of glycolysis and acid resistance, RA-FLS cells are especially sensitive to glucose and highly dependent on glycolysis and have a tenacious vitality advantage, which is the main factor for the rapid proliferation and invasion of inflammatory synovium .…”

Phenotype-Genotype analysis of caucasian patients with high risk of osteoarthritis

“…The largest single-SNP–multi-traits are 10.5164 for KIAA1211 (chr4-57072329), 9.75 for SLC4A4 (chr4-72371592), and 10.08 for RP11-333A23.4 (chr8-71393927). Functional assays showed that solute carrier family 4 members 4 (SLC4A4) might serve as a potent Rheumatoid Arthritis-specific target ( Torres et al, 2022 ). KIAA1211, also known as Cancer-related Regulator of Actin Dynamics (or CRAD), was found to regulate cell proliferation and apoptosis in non-small cell lung cancer (NSCLC) in vitro and in vivo ( Liu et al, 2019 ).…”

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

“…In this regard, the metabolic intermediate of mitochondrial TCA, succinate has been related to changes in DNA methylation and associated histone proteins, which in turn regulate gene expression [ 240 ]. In relation, Torres et al described the switch in the epigenetic environment of genes associated to the regulation of nutrient transporters in RA synoviocytes [ 241 ].…”

“…Additionally, NF-κB could restrict inflammasome activation via elimination of damaged mitochondria through p-62-dependent clearance of damaged mitochondria as well as autophagy modulate NF-κB activation [ 135 ]. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that mitochondria are involved in epigenetic regulation [ 241 ]. Natural bioactive agents of a healthy diet could protect mitochondria and inhibit the overactivation of mitochondrial oxidative stress and the associated inflammatory response that define RA.…”