Crosstalk Among circRNA/lncRNA, miRNA, and mRNA in Osteoarthritis

Abstract

Osteoarthritis (OA) is a joint disease that is pervasive in life, and the incidence and mortality of OA are increasing, causing many adverse effects on people's life. Therefore, it is very vital to identify new biomarkers and therapeutic targets in the clinical diagnosis and treatment of OA. ncRNA is a nonprotein-coding RNA that does not translate into proteins but participates in protein translation. At the RNA level, it can perform biological functions. Many studies have found that miRNA, lncRNA, and circRNA are closely related to the course of OA and play important regulatory roles in transcription, post-transcription, and post-translation, which can be used as biological targets for the prevention, diagnosis, and treatment of OA. In this review, we summarized and described the various roles of different types of miRNA, lncRNA, and circRNA in OA, the roles of different lncRNA/circRNA-miRNA-mRNA axis in OA, and the possible prospects of these ncRNAs in clinical application.

Keywords: circRNA; lncRNA; lncRNA/circRNA-miRNA-mRNA axis; miRNA; osteoarthritis.

FIGURE 1

Formation and mechanism of miRNA. miRNAs are first transcripted into longer primary miRNAs in the nucleus and then processed into hairpin RNAs of 60–70 nucleotides in the nucleus by Drosha, Pasha et al. The precursor miRNAs are transported out of the cell nucleus with the help of the Ran-GTP-dependent nucleoplasmic/cell transporter Exprotin-5 and split into 21–25 nucleotide length double-stranded miRNAs in the cytoplasm by Dicer. Subsequently, the double helix is derotated by the action of the derotation enzyme, and one of the strands is integrated into the RNA-induced silencing complex (RISC), an asymmetric RISC assembly is formed, and the other chain is immediately degraded.

FIGURE 2

Role of lncRNAs: 1. Epigenetic regulation: (A). lncRNA recruits chromatin remodeling and modification complexes to specific sites; regulates DNA or RNA methylation status, chromosome structure; and promotes the expression of related genes.2. Transcriptional regulation: (B). lncRNA can help generate mature mRNA by promoting the binding of pre-mRNA to alternative splicing factors; (C). ncRNA binding with transcription factors can inhibit the activity of target genes and inhibit their gene expression. 3. Post-transcriptional regulation: (D). Participation in mRNA translation; (E). Involvement in mRNA degradation. 4. Regulation of miRNA: (F). ncRNA can act as sponges of miR-compete for miR and alleviate the inhibition of target genes.

FIGURE 3

Biological functions of circRNA: (A). Regulation of gene transcription: Elcircrna can interact with small nuclear ribonucleoproteins and bind to RNA polymerase II; (B). miRNA sponge: circRNA contains miRNA binding sites, which can block miRNA binding to mRNA and promote or inhibit the expression of related genes by sponging miRNA; (C). circRNAs bind to mRNA regulatory binding protein, which influences the stability of mRNA, and may change the splicing pattern of circRNA; (D). By being translated by ribosomes and encoding polypeptides, several circRNAs can play a role in regulating and controlling human physiological processes.

FIGURE 4

lncRNA–miRNA–mRNA axis in OA. lncRNA can combine with miRNA to promote the expression of related target genes. PTEN = phosphatase and tensin homolog; FUT2 = fucosyltransferase 2; Timp2 = tissue inhibitor of metalloproteinase 2; KDM5C = lysine demethylase 5C; DNMT3A = DNA methyltransferase 3A; TLR4 = toll-like receptor 4; CCND1 = cyclin D1; KLF4 = Krüppel-like factor 4; SYVN1 = synoviolin 1; PPARGC1B = PPARG coactivator 1 beta; H3F3B = H3 histone family 3B; PGRN = progranulin; DNM3OS = dynamin 3 opposite strand; BMPR2 = bone morphogenetic protein receptor 2.

FIGURE 5

circRNA–miRNA–mRNA axis in OA. circRNAs can combine with miRNAs to promote the expression of related target genes. (A) circRNAs that play a role in cell proliferation and apoptosis. (B) circRNAs that play a role in degradation of the extracellular matrix and apoptosis. (C) circRNAs that play a role in degradation of the extracellular matrix, cell proliferation, apoptosis, and inflammation. NAMPT = nicotinamide phosphoribosyltransferase; MMP13 = matrix metalloproteinase.