The Expression of Non-Coding RNAs and Their Target Molecules in Rheumatoid Arthritis: A Molecular Basis for Rheumatoid Pathogenesis and Its Potential Clinical Applications

Abstract

Rheumatoid arthritis (RA) is a typical autoimmune-mediated rheumatic disease presenting as a chronic synovitis in the joint. The chronic synovial inflammation is characterized by hyper-vascularity and extravasation of various immune-related cells to form lymphoid aggregates where an intimate cross-talk among innate and adaptive immune cells takes place. These interactions facilitate production of abundant proinflammatory cytokines, chemokines and growth factors for the proliferation/maturation/differentiation of B lymphocytes to become plasma cells. Finally, the autoantibodies against denatured immunoglobulin G (rheumatoid factors), EB virus nuclear antigens (EBNAs) and citrullinated protein (ACPAs) are produced to trigger the development of RA. Furthermore, it is documented that gene mutations, abnormal epigenetic regulation of peptidylarginine deiminase genes 2 and 4 (PADI2 and PADI4), and thereby the induced autoantibodies against PAD2 and PAD4 are implicated in ACPA production in RA patients. The aberrant expressions of non-coding RNAs (ncRNAs) including microRNAs (miRs) and long non-coding RNAs (lncRNAs) in the immune system undoubtedly derange the mRNA expressions of cytokines/chemokines/growth factors. In the present review, we will discuss in detail the expression of these ncRNAs and their target molecules participating in developing RA, and the potential biomarkers for the disease, its diagnosis, cardiovascular complications and therapeutic response. Finally, we propose some prospective investigations for unraveling the conundrums of rheumatoid pathogenesis.

Keywords: RANK-RANKL-OPG signaling; Wnt/β-catenin pathway; anti-citrullinated protein antibody; bone-marrow-derived stem cell; fibroblast-like synoviocyte; non-coding RNA; peptidylarginine deiminase; rheumatoid arthritis.

Figure 1

The mechanisms of APCA in eliciting development of rheumatoid arthritis. (A) Preformed immune complexes composed of circulating ACPA and citrullinated proteins bind to FcγR or bind directly to the surface-expressed cit-GRP78 on the macrophage. These two types of binding can stimulate TNF-α production from macrophages. In addition, a direct binding of ACPA to cit-HSP-60 on OB activates IL-6 and IL-8 secretion from OB and subsequently induces cell apoptosis and inflammation; (B) ACPA can directly activate OC to induce bone destruction and elicit neighboring chondrocyte apoptosis after its binding; (C) ACPA can bind to neutrophils and induce NETosis; (D) ACPA can activate the complement system to induce inflammation. ACPA: anti-citrullinated protein antibody (green in color). ACPA: anti-citrullinated protein antibody, OB: osteoblast, OC: osteoclast, Mϕ: macrophage, PMN: polymorphonuclear neutrophil, FcγR: IgG Fragment C receptor, IC: immune complex, TNF: tumor necrosis factor, IL: interleukin, cit-GRP78: citrullinated glucose-regulated protein 78, cit-HSP-60: citrullinated heat shock protein 60, NET: neutrophil extracellular trap.

Figure 2

The individual functions of microRNAs (miRs) and long non-coding RNAs (lncRNAs), and their cross-talk for fine-tune regulation of the gene expression. The larger molecule of lncRNAs not only exhibit their own specific epigenetic regulatory power but act as sponges to modulate specific miR’s functions for achieving the fine-tune modifications of the gene expression.

Figure 3

The signaling pathways of Toll-like receptors (TLRs) and their regulations by intracellular ncRNAs in innate immune responses. The molecules released from microbial pathogens (pathogen-associated molecular pattern, PAMPs) or endogenous danger molecules released from damaged cells (damage-associated molecular pattern, DAMP) can bind to TLRs and then activate intracellular adaptor molecules MyD88 or TRIF. A number of ncRNAs may participate in the modulation of NF-κB and IRF3/7 which enter the nucleus to determine the futures of macrophages differentiation to proinflammatory M1 or anti-inflammatory M2 subpopulation. MyD88: myeloid differentiation factor 88, TRIF: Toll/IL-1 receptor-containing adaptor inducing IFN-β, IRF: interferon regulatory factor.

Figure 4

The involvement of intracellular microRNAs (miRs) in the T cell differentiation and T cell release of exosomal and plasma miRs during the development of rheumatoid arthritis (RA). The T cell subpopulations include the total CD4⁺T, Th17, and regulatory T cell. ↑: Increase, ↓: Decrease.

Figure 5

The involvement of intracellular long non-coding RNAs (lncRNAs) in the T and B cell differentiation and T cell release of exosomal and plasma miRs during the development of RA. The immune cell subpopulations include CD4⁺T, Th17, and B cell. ↑: Increase, ↓: Decrease.

Figure 6

The effects of inflammation on ncRNA expressions and on the biological behavioral changes of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) that are relevant to RA pathogenesis. The biological behavioral changes of RA-FLSs include increased cell proliferation, decreased cell apoptosis, enhanced cell invasion, and augmenting proinflammatory cytokine productions. ↑: Increase, ↓: Decrease.

Figure 7

The effects of exosomes released from bone-marrow-derived mesenchymal stem cells (BM-MSCs) on the changes in biological behavior of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). The extruded exosomes containing ncRNAs are enclosed by a lipid bilayer and can move, attach, and merge into the remote RA-FLSs to influence their biological behaviors. Some of the miRs can then suppress inflammatory responses, chemotaxis, and biological behaviors of RA-FLSs.

Figure 8

The effects of RA-FLS-released microRNAs (miRs) and their target molecules on the changes in biological behaviors of osteoblasts (OBs), osteoclasts (OCs), and chondrocytes. These aberrant-expressed miRs can target crucial molecules and impair bone regeneration, increase bone destruction, and decrease cartilage repair. SATB2: special AT-rich sequence binding protein 2, Sp7: specificity protein 7, OPG: osteoprotegerin, RANKL: receptor for activator of NF-κB ligand, PDK4: pyruvate dehydrogenase kinase 4.

Figure 9

The beneficial effect of RA-FLS-released ncRNAs including miR-218, Exo-miR-486-5p, miR-9, and FOXM-LINC 00152 with their target molecules on the osteogenic differentiation. Increased expression of the ROBO/DKK axis, BMP/Smad signaling and Wnt/β-catenin signaling, and decreased RANKL/OPG ratio are positive for bone regeneration. ROBO1: roundabout guidance receptor 1, Smad: small mother against decapentaplegic protein, BMP: bone morphogenetic protein, DKK: Dickkopf, ↑: Increase, ↓: Decrease.

Figure 10

The clinical applications of aberrant ncRNA expressions in patients with RA. These aberrant ncRNA expressions can be used as the biomarkers for disease diagnosis, CV complications, and therapeutic responses. The therapeutic response biomarkers can be further divided into two groups, methotrexate (MTX) responders and TNF-α blocker responders. The increased miR-27a-3p expression is quite unique and can become a biomarker for both groups. ↑: Increase, and ↓: Decrease.