Involvement of Long Non-Coding RNAs in the Pathogenesis of Rheumatoid Arthritis

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Involvement of Long Non-Coding RNAs in the Pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease that brings about progressive joint destruction, systemic complications, and a reduced life expectancy. Despite significant progress in understanding its pathogenesis and improvements in treatment, there are still limitations. The mechanisms of RA are not fully clear, and joint destruction can persist even after aggressive treatment. Toxicity from immunosuppressive agents also contributes to high mortality. Thus, exploring the pathogenesis is crucial for finding new treatment targets.

The field of epigenetics has uncovered the regulatory roles of noncoding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs), being over 200 nucleotides in length, are a class of ncRNAs. Emerging evidence indicates their involvement in RA development.

LncRNA in RA Fibroblast-Like Synoviocytes (FLSs)

RA FLSs are major components in synovial tissue. They produce cytokines for local inflammation and proteolytic enzymes to degrade the extracellular matrix. Their increased proliferation, migration, invasion, and decreased apoptosis are key features. LncRNAs play regulatory roles here:

  • LERFS: A newly identified lncRNA in RA FLSs via microarray analysis. Its decreased expression negatively regulates proliferation, migration, and invasion. It interacts with hnRNP Q (an RNA-binding protein) to form a complex that affects the mRNAs of RhoA, Rac1, and Cdc42, reducing their stability or translation. This shows its role in synovial aggression and hyperplasia in RA.
  • C5T1lncRNA: Identified within the TRAF1-C5 region (a susceptibility locus for RA). In RA FLSs, it suppresses the mRNA of C5 (a protein detected in inflamed joints). However, its expression in RA or OA FLSs is comparable, and its inflammation-specific role and functional role in RA need further validation.
  • GAPLINC: Previously linked to tumor cell proliferation and metastasis. Its increased expression in RA FLSs promotes proliferation, in vitro migration, and invasion. Bioinformatics analysis suggests it could act as a molecular sponge for miR-382–5p and miR-575, and it may regulate signaling pathways like MAPK, Ras, and PI3K-Akt. But the regulatory effect on RA FLSs’ biological behavior based on cancer cell findings needs verification.
  • MALAT1: Involved in regulating inflammation and cell proliferation of RA FLSs. It may also promote apoptosis. It acts through two signaling pathways: binding to the CTNNB1 promoter region to affect b-catenin (a key molecule in the Wnt signaling pathway) and influencing the PI3K/AKT pathway when down-regulated.
  • LncRNA-IL7R: Exerts pro-proliferation and anti-apoptosis effects. It increases the binding of enhancer of zeste homolog 2 (EZH2) and H3K27me3 levels across cyclin-dependent kinase inhibitor promoters, suppressing their transcription.
  • ITSN1-2: Up-regulated in RA synovial tissue and FLSs. Knockdown inhibits proliferation and promotes apoptosis. It is correlated with pro-inflammatory cytokines and negatively with IL-10. GO and KEGG enrichment analysis found many differentially expressed genes (DEGs) regulated by its knockdown, with NOD2 being a top DEG associated with inflammation.
  • ZFAS1: Contributes to the invasive phenotype of RA FLSs. It positively regulates the activity of MMP-2 and MMP-9. By suppressing miR-27a (whose expression is decreased in RA synovial tissue and FLSs), it promotes in vitro migration and invasion.
  • UCA1: Decreased expression is associated with reduced caspase-3 activity, increasing cell viability. Wnt6 is a mediator through which it regulates apoptosis.
  • HOTAIR: Its expression in RA is context-dependent. It increases in PBMC and blood exosomes, and stimulated macrophages show enhanced migration. It is decreased in FLSs and osteoclasts, and overexpression suppresses MMP activation. It also inhibits inflammation and promotes proliferation in LPS-induced chondrocytes (possibly via the NF-kB signaling pathway through miR-138).
  • GAS5: Overexpression in RA FLSs promotes apoptosis by activating caspases and suppressing the PI3K/AKT pathway. However, its expression in T cells and serum in RA is inconsistent.
  • DILC: Negatively correlated with serum IL-6. Similar to GAS5, it induces apoptosis of RA FLSs.
  • PVT1: In a rat CIA model, its knockdown suppresses pro-inflammatory cytokine production, inhibits cell proliferation, and promotes apoptosis. Bioinformatics prediction and dual-luciferase reporter gene assay found sirt6 (a gene involved in inflammation and bone destruction) as a target. Down-regulation of PVT1 hinders sirt6 methylation. But its role in RA FLSs’ invasiveness needs direct proof.

LncRNA in Lymphocytes from RA

The synovium of RA has many lymphocytes, with T lymphocytes (especially Th1 and Th17) being major mediators. LncRNAs play roles here:

  • NEAT1: Upregulation induces Th17 cell differentiation. Knockdown has a protective effect in mice CIA models. It stabilizes STAT3 protein levels, skewing the immune repertoire to Th17 cells.
  • LncRNA-p21: In RA, its expression is low and can be restored by MTX treatment. It sequesters RELA mRNA, interfering with its translation and suppressing NF-kB activation.
  • LOC100506036: Increased expression in peripheral T cells in RA. It promotes IFN-γ production (possibly by suppressing SMPD1 protein).
  • THRIL and RMBP: Upward trends in T cells from RA patients. They are suggested as biomarkers for RA, with RMRP also correlated with disease duration.

LncRNA in Monocyte-Derived Macrophages from RA

Macrophages contribute to cytokine storm and cartilage/bone destruction in RA. LncRNAs are involved in their differentiation:

  • NTT: Increased expression in PBMC from untreated early RA patients. Overexpression enhances PBOV1 expression, facilitating monocyte to macrophage differentiation and chemokine production. The C/EBPb/NTT/PBOV1 axis activation is correlated with high disease activity.
  • GAS5: Its increased expression in T cells from RA PBMC (but subsets not specified). Its role in T cells from RA needs determination in larger sample sizes.

LncRNA in Chondrocytes from RA

Chondrocytes maintain cartilage matrix. LncRNAs are involved in their regulation:

  • MEG3: Involved in regulating inflammation in RA. Its expression is suppressed in LPS-stimulated chondrocytes, and overexpression inhibits pro-inflammatory cytokine production. It also promotes proliferation and relieves extracellular matrix degradation in OA chondrocytes. However, its role in RA FLSs is controversial and needs further research.
  • HOTAIR: Its involvement in RA chondrocytes is discussed earlier.

Other lncRNAs detected in RA PBMC or synovial cell lines include:

  • Lnc-COX2: Positively correlated with serum IL-6 and MMP-9 levels.
  • lnc0640 and lnc5150: Associated with CRP levels. TT genotype of rs13039216 in lnc0640 gene is associated with reduced RA risk.
  • NR024118: Involved in regulating inflammatory cytokines and MMPs. Inhibition suppresses mRNA expression of IL-6, IL-8, MMP-1, and MMP-3 in MH7A synovial cell lines.

LncRNA in Signaling Pathways Involved in RA

Two key signaling pathways (NF-kB and RhoGTPases) are highlighted:

  • NF-kB signaling pathway: LncRNA-p21 and lncRNA-COX2 are implicated. LncRNA-p21 suppresses inflammation by sequestering NF-kB. LncRNA-COX2 forms a positive feedback loop in macrophages, and its knockdown affects histone methylation.
  • RhoGTPases signaling pathway: LncRNAs like LERFS, MEG3, and MALAT1 are involved. LERFS affects RhoA, Rac1, and Cdc42 expression. MEG3 and MALAT1 may regulate RA FLSs through this pathway (but further study needed).

Conclusions

LncRNAs are important regulators in RA. Exploring their aberrant expression profiles, functional roles, and modes of action will deepen our understanding of RA. Some lncRNAs are associated with clinical indicators, suggesting they could be biomarkers. Their validity needs verification in large RA populations. Many lncRNAs are candidate regulators in inflammatory signaling pathways, but only a few are tested in RA. The shared mechanisms with other inflammatory diseases imply similar lncRNA roles. Manipulating lncRNAs shows beneficial effects in animal models, indicating their potential as treatment targets. Research on lncRNAs in RA is a nascent field, and further study will likely lead to new insights and therapeutic avenues.

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