Involvement of Long Non-Coding RNAs in the Pathogenesis of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint destruction, systemic complications, and reduced life expectancy. Despite significant advancements in understanding its pathogenesis and treatment, the mechanisms underlying RA remain incompletely elucidated. Current therapies, including conventional and biological treatments, have limitations, as joint destruction persists in some patients even after aggressive treatment. Additionally, the toxicity associated with immunosuppressive agents contributes to the high mortality rate in RA patients. Therefore, exploring the molecular mechanisms that initiate and perpetuate RA is crucial for identifying novel therapeutic targets.
Recent research has highlighted the regulatory roles of non-coding RNAs (ncRNAs) in various biological processes, including RA pathogenesis. Among ncRNAs, long non-coding RNAs (lncRNAs), which are transcripts longer than 200 nucleotides, have emerged as key players in the regulation of gene expression and cellular functions. This review summarizes the current findings on the involvement of lncRNAs in RA, focusing on their roles in cellular functions, signaling pathways, and potential as biomarkers and therapeutic targets.
Classification and Functions of lncRNAs
LncRNAs are classified into five categories based on their genomic location relative to protein-coding genes: long intergenic ncRNAs (lincRNAs), intronic lncRNAs, bidirectional lncRNAs, sense-overlapping lncRNAs, and natural antisense lncRNAs. These lncRNAs are involved in a wide range of biological activities, including epigenetic regulation, chromatin remodeling, and transcriptional and post-transcriptional modifications. The GENCODE database (version 31) identifies 17,904 lncRNA genes in humans, underscoring their potential regulatory significance.
lncRNAs in RA Fibroblast-Like Synoviocytes (FLSs)
Fibroblast-like synoviocytes (FLSs) are major components of synovial tissue in RA. Unlike normal FLSs, RA FLSs exhibit aggressive phenotypes, including increased proliferation, migration, invasion, and decreased apoptosis. These cells also produce abundant cytokines and proteolytic enzymes that promote local inflammation and extracellular matrix degradation. Several lncRNAs have been implicated in regulating the biological functions of RA FLSs.
LncRNA LERFS
LERFS, a newly identified lncRNA, is downregulated in RA FLSs. It negatively regulates the proliferation, migration, and invasion of RA FLSs by interacting with hnRNP Q, an RNA-binding protein. This interaction reduces the stability or translation of mRNAs encoding RhoA, Rac1, and Cdc42, which are involved in cell motility. The downregulation of LERFS contributes to synovial aggression and hyperplasia in RA.
LncRNA C5T1lncRNA
C5T1lncRNA, located within the TRAF1-C5 region, suppresses the mRNA of C5, a protein detected in inflamed joints of RA patients. Mice deficient in C5 are resistant to collagen-induced arthritis (CIA). However, the expression of C5T1lncRNA and C5 in FLSs from RA and osteoarthritis (OA) patients is comparable, suggesting that its role in RA requires further validation.
LncRNA GAPLINC
GAPLINC is upregulated in RA FLSs and promotes their proliferation, migration, and invasion. It acts as a molecular sponge for miR-382-5p and miR-575, which are negatively correlated with GAPLINC expression. Bioinformatics analysis suggests that GAPLINC regulates signaling pathways such as MAPK, Ras, and PI3K-Akt, which are involved in cell proliferation and motility.
LncRNA MALAT1
MALAT1 is downregulated in RA FLSs and suppresses inflammation and proliferation. It inhibits the transcription of CTNNB1 by recruiting methyltransferase to its promoter region, thereby preventing the activation of the Wnt signaling pathway. MALAT1 also promotes apoptosis in RA FLSs by suppressing apoptosis-associated proteins such as caspase-3, caspase-9, Bax, and Bcl-2.
LncRNA-IL7R
LncRNA-IL7R is upregulated in RA FLSs and promotes their proliferation while suppressing apoptosis. It increases the binding of EZH2 and H3K27me3 to the promoters of p16 and p21, inhibiting their transcription. This mechanism contributes to the aggressive phenotype of RA FLSs.
LncRNA ITSN1-2
ITSN1-2 is upregulated in RA synovial tissue and FLSs. Its knockdown inhibits proliferation and promotes apoptosis in RA FLSs. ITSN1-2 is positively correlated with pro-inflammatory cytokines such as TNF-α and IL-17 and negatively correlated with IL-10. It regulates pathways related to RA, including the NOD2 signaling pathway.
LncRNA ZFAS1
ZFAS1 promotes the invasive phenotype of RA FLSs by increasing the activity of matrix metalloproteinases (MMPs) MMP-2 and MMP-9. It suppresses miR-27a, which is downregulated in RA synovial tissue and FLSs, thereby enhancing cell migration and invasion.
LncRNA UCA1
UCA1 is downregulated in RA FLSs and promotes apoptosis by increasing the activity of caspase-3. It regulates apoptosis through the Wnt6 signaling pathway.
LncRNA HOTAIR
HOTAIR expression is context-dependent in RA. It is upregulated in peripheral blood mononuclear cells (PBMCs) and blood exosomes but downregulated in FLSs and osteoclasts. HOTAIR suppresses the activation of MMP-2 and MMP-13 in FLSs and osteoclasts and inhibits inflammation in LPS-induced chondrocytes by suppressing the NF-κB signaling pathway through miR-138.
LncRNA GAS5
GAS5 is downregulated in RA FLSs and promotes apoptosis by activating caspase-3 and caspase-9 and suppressing the PI3K/Akt signaling pathway. However, its expression is inconsistent in T cells and serum from RA patients, suggesting a need for further research.
LncRNA DILC
DILC is negatively correlated with serum IL-6 and induces apoptosis in RA FLSs.
LncRNA PVT1
PVT1 is upregulated in the synovial tissue of CIA rats and promotes the production of pro-inflammatory cytokines such as TNF-α and IL-1β in RA FLSs. It also inhibits apoptosis and promotes proliferation by regulating the methylation of sirt6, a gene involved in inflammation and bone destruction.
lncRNAs in Lymphocytes from RA
T lymphocytes, particularly Th1 and Th17 cells, play a crucial role in initiating RA by promoting the release of inflammatory cytokines. Several lncRNAs have been implicated in the regulation of T lymphocytes in RA.
LncRNA NEAT1
NEAT1 is upregulated in RA and induces the differentiation of Th17 cells. It stabilizes the protein level of STAT3, which skews the immune repertoire towards Th17 cells. NEAT1 knockdown protects against arthritis development in CIA mice.
LncRNA-p21
LncRNA-p21 is downregulated in RA and suppresses inflammation by sequestering NF-κB. Methotrexate (MTX) restores lncRNA-p21 expression, thereby inhibiting NF-κB activation and reducing inflammation.
LncRNA LOC100506036
LOC100506036 is upregulated in peripheral T cells from RA patients and promotes the production of IFN-γ by suppressing SMPD1 protein.
LncRNA THRIL and RMRP
THRIL and RMRP are upregulated in T cells from RA patients and are suggested as biomarkers for RA. RMRP is also correlated with disease duration.
lncRNAs in Monocyte-Derived Macrophages from RA
Macrophages in RA synovial tissue contribute to cytokine production and cartilage destruction. LncRNA NTT is upregulated in PBMCs from untreated early RA patients and promotes the differentiation of monocytes into macrophages by enhancing the expression of PBOV1. The C/EBPβ/NTT/PBOV1 axis is correlated with high disease activity in RA.
lncRNAs in Chondrocytes from RA
Chondrocytes regulate cartilage matrix turnover in RA. LncRNA MEG3 is downregulated in LPS-induced chondrocytes and inhibits the production of pro-inflammatory cytokines such as IL-17 and IL-23. It also suppresses the AKT-mTOR signaling pathway, promoting chondrocyte proliferation and inhibiting inflammation.
lncRNAs in Signaling Pathways Involved in RA
NF-κB Signaling Pathway
NF-κB is a master regulator of inflammation in RA. LncRNA-p21 and lncRNA-COX2 are involved in the regulation of NF-κB signaling. LncRNA-p21 suppresses NF-κB activation by sequestering RelA mRNA, while lncRNA-COX2 transactivates late-primary response genes following NF-κB activation.
RhoGTPases Signaling Pathway
RhoGTPases regulate cell motility in RA. LncRNA LERFS interferes with the expression of RhoA, Rac1, and Cdc42 through hnRNP Q, thereby regulating cell migration and invasion. LncRNA MEG3 and MALAT1 also regulate RhoGTPases in tumor cells, suggesting their potential roles in RA FLSs.
Conclusion
Emerging evidence highlights the significant roles of lncRNAs in the pathogenesis of RA. These lncRNAs regulate various cellular functions, including proliferation, migration, invasion, apoptosis, and inflammation, in RA FLSs, lymphocytes, macrophages, and chondrocytes. They are also involved in key signaling pathways such as NF-κB and RhoGTPases. Furthermore, lncRNAs show potential as biomarkers for monitoring disease activity and as therapeutic targets for RA. Continued research on lncRNAs will likely provide novel insights into RA pathogenesis and lead to the development of new therapeutic strategies.
doi.org/10.1097/CM9.0000000000000755
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