Altered fibroblast-like synoviocyte epigenetics is responsible for deficient NUB1 expression in rheumatoid arthritis

TL;DR

This study shows that reduced NUB1 expression in rheumatoid arthritis is due to epigenetic changes in synovial cells, leading to increased inflammation.

Contribution

The novel finding is that defective NUB1 induction in rheumatoid arthritis is caused by an altered epigenetic landscape in fibroblast-like synoviocytes.

Findings

NUB1 expression is reduced in rheumatoid arthritis synovium compared to osteoarthritis tissue.

Epigenetic inhibitors like 5-azacytidine and EPZ6438 can partially or fully restore NUB1 induction in rheumatoid fibroblast-like synoviocytes.

Defective NUB1 induction is linked to increased neddylation and IL-6 expression in rheumatoid synovium.

Abstract

Neddylation is a post-translational modification suppressed by the endogenous inhibitor NUB1, and its dysregulation in rheumatoid arthritis (RA) promotes inflammation and NF-κB activation. NUB1 expression in RA and osteoarthritis (OA) synovium and mechanisms underlying defective NUB1 induction in RA fibroblast-like synoviocytes (FLS) were evaluated. NEDD8 and IL-6 protein expression was increased and NUB1 was reduced in RA synovium compared with OA tissue, with significant differences in the lining region that correlated with higher cytokine expression and NF-kB translocation. IL-1β–induced NUB1 induction was impaired in RA FLS at both the mRNA and protein levels. To evaluate the mechanism, we assessed mRNA stability using actinomycin D, examined the role of SNHG12 by siRNA knockdown, analyzed MAP kinase signaling, and measured NUB1 promoter activity with a luciferase reporter assay. None could explain the reduced induction observed in RA FLS. Treatment with the DNA methylation inhibitor 5-azacytidine and the histone methylation inhibitor EPZ6438 partially reversed the difference in NUB1 induction, whereas the histone deacetylase inhibitors ITF2375 and MS275 eliminated it. Therefore, defective NUB1 induction in RA FLS is related to the aberrant epigenetic landscape in RA FLS and is associated with increased neddylation and increased IL-6 expression in rheumatoid synovium. Overcoming increased neddylation in RA represents a novel therapeutic approach.

The online version contains supplementary material available at 10.1038/s41598-026-38420-y.

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