Involvement of long non-coding RNAs in the pathogenesis of rheumatoid arthritis

Abstract

Long non-coding RNA (lncRNA) plays a contributory role in rheumatoid arthritis (RA). In this review, we summarized the current findings of lncRNAs in RA, including cellular function and the potential mechanisms. Serum lncRNA levels are associated with serum proinflammatory cytokines and disease activity. LncRNAs regulate proliferation, migration, invasion and apoptosis of RA fibroblast-like synoviocytes (FLSs), modulate the differentiation of T lymphocytes and macrophages, and affect bone formation-destruction balance of chondrocytes. Besides, lncRNAs are involved in inflammation and cell motivation signaling pathways. In-depth research on lncRNAs may help elucidate the pathogenesis of RA and provides clues for novel treatment targets.

Figure 1

The classification of lncRNA. LncRNA can be subcategorized according to their relationship associated to the protein coding genes. (A) Intergenic lncRNAs are transcribed from the location between annotated protein-coding genes. (B) Intronic lncRNAs are RNA molecules that originate from the intron coding genes in either sense or antisense orientation. (C) Bidirectional lncRNAs are oriented from a location close to protein-coding genes but to an opposite direction. (D) Sense overlapping lncRNAs are transcribed from and overlapped with the sense strands of protein-coding genes. (E) Natural antisense lncRNAs are transcribed from the antisense strands and overlapped with one or several exons/introns. lncRNAs: Long noncoding RNAs.

Figure 2

Cellular function of lncRNA. (A) LncRNAs recruit chromatin modifiers to regulate the epigenetic modification such as methylation and acetylation of the chromatin, altering the accessibility of genes to DNA-binding proteins and thus, interfering gene transcription. (B) LncRNAs can bind to the transcriptional factors to promote or inhibit their activity to interact with the promoter regions of certain genes. (C) LncRNAs interfere the transcriptional function of RNA polymerase II (Pol II). (D) LncRNAs are involved in the formation of some subnuclear structures such as paraspeckles to release their suppressive effect on DNA transcription. (E) The regulatory roles of lncRNA on mRNA translation are multifactorial. LncRNAs have impact on pre-mRNA splicing. LncRNAs modulate mRNA stability by associating with proteins involved in mRNA degradation. LncRNAs also function as sponge to miRNA and reverse their inhibitory effect on mRNA translation. LncRNA can recruit translational repressors to block the binding between mRNA and ribosome. (F) LncRNAs regulate protein phosphorylation at post-translation level in cytoplasm. lncRNAs: Long noncoding RNAs; miRNAs: microRNAs.

Figure 3

Functional lncRNAs in signaling pathway. (A) LncRNAs regulate NF-κB signaling pathways. NKILA masks the phosphorylating sites of IKKβ in IκBα-RelA complex and suppresses RelA activation. LncRNA-p21 sequesters RelA by suppressing its mRNA translation. Lethe blocks the DNA-binding activity of RelA homodimer. PACER sequesters p50 and facilitates the formation of Pol II transcriptional complex. LncRNA-Cox2 is integrated into the SWI/SNF complex and transactivates late-primary response genes regulated by NF-κB. CAMK-A, in accompany with calmodulin-dependent kinase PNCK, promotes IκBα phosphorylation and nuclear transportation of RelA. (B) LncRNAs participate in the regulation of RhoGTPases-mediating pathways. Newly-identified lncRNA LERFS forms a complex with hnRNP Q to interfere the translation of RhoA, Rac1, and Cdc42. NORAD, MEG3, shlnc-EC6, H19, and MALAT1 act as miRNA sponges to regulate the translation of the aforementioned RhoGTPases, respectively. IKK: Inhibitory-κB kinase; lncRNA: Long non-coding RNA; NEMO: NF-κB essential modulator; NF: Nuclear factor; NKILA: NF-κB interacting lncRNA; PNCK: Pregnancy upregulated non-ubiquitous calmodulin kinase.