A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis

Abstract

The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.

Transcriptional regulation of human amelotin gene by interleukin‐1β

“…YY1 is a ubiquitous and multifunctional zinc‐finger transcription factor of the Polycomb group protein family . TNF‐α and IL‐1β promoted YY1 expression in the fibroblast‐like synoviocytes of rheumatoid arthritis patients . We have identified C/EBPβ and YY1 as transcription factors that are important for human AMTN gene transcription regulated by IL‐1β in this study.…”

DDR2–CYR61–MMP1 Signaling Pathway Promotes Bone Erosion in Rheumatoid Arthritis Through Regulating Migration and Invasion of Fibroblast-Like Synoviocytes

“…Accumulating evidence indicates that RA FLS display tumor‐like phenotypes such as aggressive growth, apoptosis resistance, migration, and invasion, which is a critical feature of FLS for synovial hyperplasia and cartilage erosion . In addition, FLS may participate in both synovial inflammation and bone erosion in RA by production of dozens of inflammatory cytokines like IL‐1β, TNFα, IL‐6, IL‐8, and MMP molecules such as MMP1 and MMP13 . Therefore, modulating the aggressive behaviors of FLS may provide a novel advantage in the treatment of RA.…”

“…(27) In addition, FLS may participate in both synovial inflammation and bone erosion in RA by production of dozens of inflammatory cytokines like IL-1b, TNFa, IL-6, IL-8, and MMP molecules such as MMP1 and MMP13. (7,17,28) Therefore, modulating the aggressive behaviors of FLS may provide a novel advantage in the treatment of RA.…”

Review: The Tumor‐Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine

“…Noncoding RNA (ncRNA), including miRNA and long noncoding RNA (lncRNA), is an epigenetic regulatory mechanism that imparts broad and long‐term changes in gene expression. In Table , miRNAs and lncRNAs are categorized according to 3 major pathologic features of rheumatoid FLS: 1) inflammation, 2) proliferation and survival, and 3) tissue invasiveness, and the common functional roles of ncRNAs identified both in rheumatoid FLS and in cancer cells are highlighted. MicroRNA 221 (miR‐221), for instance, is overexpressed in both cell types; it promotes tissue invasiveness by up‐regulating MMPs in rheumatoid FLS and it increases the migration of metastatic cancer cells .…”