Unraveling the impact of miRNAs on gouty arthritis: diagnostic significance and therapeutic opportunities

Abstract

Gouty arthritis is a prevalent inflammatory illness. Gout attacks begin when there is an imbalance in the body's uric acid metabolism, which leads to urate buildup and the development of the ailment. A family of conserved, short non-coding RNAs known as microRNAs (miRNAs) can regulate post-transcriptional protein synthesis by attaching to the 3' untranslated region (UTR) of messenger RNA (mRNA). An increasing amount of research is pointing to miRNAs as potential players in several inflammatory diseases, including gouty arthritis. miRNAs may influence the progression of the disease by regulating immune function and inflammatory responses. This review mainly focused on miRNAs and how they contribute to gouty arthritis. It also looked at how miRNAs could be used as diagnostic, prognostic, and potential therapeutic targets.

Keywords: Biomarker; Diagnosis; Gouty arthritis; Therapy; miRNA.

Fig. 1

miRNA biogenesis. The pri-miRNA is converted into the precursor miRNA (pre-miRNA). The RNase III endonuclease Dicer must first digest the miRNA after it has entered the cytoplasm through Exportin 5. The functional effector complex is directed by matured miRNA in a single-stranded form to modify complementary RNA targets. Ago: argonaute1; DGCR8: DiGeorge Critical Region 8; Dicer: an endoribonuclease enzyme that in humans is encoded by the DICER1 gene; Drosha: double-stranded RNA-specific endoribonuclease; Ran: RAS-related nuclear protein; RISC: RNA-induced silencing complex; RNA Pol II: RNA polymerase II; TRBP: transactivation response element RNA-binding protein. This figure was created with BioRender (https://biorender.com/)

Fig. 2

Molecular pathways involved in gouty arthritis and potential miRNA regulators. Inflammasomes and the release of pro-inflammatory cytokines are the primary sources of inflammation associated with gout. TNF-α, certain interleukins, and NLRP3 inflammasome are involved in the development of gout. Macrophages, neutrophils, and monocytes are involved in these inflammatory amplification cascades. AKT: protein kinase B; ERK: extracellular signal-regulated kinase; GSDMD: gasdermin D; IKK: IκB kinase; IL: interleukin; IRAK1: IL-1 receptor-associated kinase; JAK: Janus kinase; MEK: mitogen-activated extracellular signal-regulated kinase; mTOR: mammalian target of rapamycin; MyD88: myeloid differentiation primary-response protein 88; NEMO: nuclear factor-kappa B essential modulator; NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; NF-κB: nuclear factor-κB; PI3K: phosphatidyl inositol 3-kinase; PTEN: phosphatase and tensin homolog; Raf: rapidly accelerated fibrosarcoma; Ras: renin angiotensin system; RhoA: Ras homolog gene family member A; ROCK: rho kinase; SIRT1: silent information regulator sirtuin 1; STAT: signal transducer and activator of transcription; TLR: toll-like receptor; TNF-α: tumor necrosis factor-alpha; TRAF: TNF receptor-associated factor. This figure was created with BioRender (https://biorender.com/)

Fig. 3

Role of miRNA in hyperuricemia. High levels of hsa-miR-155 are associated with morpho-structural alterations. hsa-miR-223 could inhibit NLRP3 expression, resulting in decreased NLRP3 inflammasome activity. hsa-miR-17 and hsa-miR-18a are involved in oncogenesis, proliferation, and activation of B-cells, T-cells, and macrophages. hsa-miR-17-5p hinders the activity of NLRP3 inflammasomes by attaching to and reducing the mRNA levels of thioredoxin-interacting protein. Decreased hsa-miR-92a inhibits vascular neogenesis by blocking the KLF2-VEGFA axis. hsa-miR-34a inhibits the expression of human URAT1. Low levels of hsa-miR-143-3p stimulate uric acid reabsorption. GLUT9: glucose transporter9; KLF2: Krüppel-like factor 2; NLRP3: NOD-like receptor protein 3; SLC22A12: solute carrier family 22 member 12; TXNIP: thioredoxin-interacting protein; URAT1: urate transporter 1; VEGFA: vascular endothelial growth factor A. This figure was created with BioRender (https://biorender.com/)

Fig. 4

Clinical importance of miRNAs in gouty arthritis. The expression of miR-142-3p was significantly elevated in both in vivo and in vitro models of GA. Elevated levels of hsa-miR-142, hsa-miR-17, hsa-miR-30c, hsa-miR-18a, and hsa-miR-223 were detected in the plasma of patients diagnosed with GA. The miR-155 was detected in the mononuclear cells of synovial fluid. The level of mmu-miR-146a expression was elevated in mouse bone marrow-derived macrophages activated by MSU crystals. This figure was created with BioRender (https://biorender.com/)

Fig. 5

Role of miRNA in treatment of gout arthritis. hsa-miR-155 acts as a proinflammatory regulator via SH2 domain-containing inositol phosphatase 1 (SHIP-1) down-regulation and provokes the production of proinflammatory cytokines, such as TNF-α and IL-1β. hsa-miR-155 promotes inflammation by targeting anti-inflammatory molecules such as SOCS1, a negative regulator of pro-inflammatory cytokines. hsa-miR-34a modulation may have an impact on urate levels and could potentially be explored as a therapeutic approach. hsa-miR-449a influences the expression of HDAC1, which mediates the generation of cytokine production in MSU crystals. hsa-miR-192-5p targets NFAT5which is associated with the activation of macrophages and TLR-promoted arthritis. hsa-miR-23a-5p enhances inflammation in gout by stimulating MyD88/NF-κB. hsa-miR-142-3p promotes the inflammatory response by binding with ZEB2 to activate the NF-κB signaling. hsa-miR-146a acts on the TLR4/MyD88/NF-KB signaling pathway. hsa-miR-3146 triggers the formation of neutrophil extracellular traps. hsa-miR-92a influences KLF2/ VEGFA. hsa-miR-663 interacts with TGF-β1 to target and control the expression of PTEN. hsa-miR-302b exerts a negative regulatory effect on the production of IL-1β. hsa-miR-488 and hsa-miR-920 have the capability to directly bind to the 3′ untranslated region (UTR) of IL-1β and particularly alter its function. hsa-miR-223-3p and hsa-miR-22-3p decrease the synthesis of IL-1β by specifically targeting NLRP3. hsa-miR-221-5p has been detected to greatly suppress the expression of TNF-α, IL-8, and IL-1β. EREG: epiregulin; IL-1β: interleukin-1 beta; IL-6: interleukin-6; KLF2: Krüppel-like factor 2; MyD88: myeloid differentiation primary-response protein 88; NETs: neutrophil extracellular traps; NFAT5: nuclear factor of activated T-cells 5; NF-κB: nuclear factor kappa B; SOCS1: suppressor of cytokine signaling 1; TGF-β1: transforming growth factor-β1; TLR2: toll-like receptor 2; TLR4: toll-like receptor 4; URAT1: urate transporter 1; VEGFA: vascular endothelial growth factor A; ZEB2: zinc finger E-box binding homeobox. This figure was created with BioRender (https://biorender.com/)