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Objectives Long non-coding RNA H19 (lncRNA-H19) is highly expressed in fibroblast-like synoviocytes (FLS) from patients with RA. The present study aimed to clarify the pathological significance and regulatory mechanisms of lncRNA-H19 in FLS. Methods Mice with CIA were locally injected with LV-shH19. The progression of CIA was explored by measuring arthritic index (AI), paw thickness (PT) and histologic analysis. The growth and cell cycle of human synoviocyte MH7A were assessed by CCK-8 and flow cytometric analysis. The putative binding sites between lncRNA-H19 and miR-124a were predicted online, and the binding was identified by luciferase assay. RT-qPCR, Western blot and luciferase assay were performed to explore the molecular mechanisms between liver X receptor (LXR), lncRNA-H19, miR-124a and its target genes. Results The expression of lncRNA-H19 was closely associated with the proliferation of synoviocytes and knockdown of lncRNA-H19 significantly ameliorated the progression of CIA, reflected by decreased AI, PT and cartilage destruction. Notably, lncRNA-H19 competitively bound to miR-124a, which directly targets CDK2 and MCP-1. It was confirmed that lncRNA-H19 regulates the proliferation of synoviocytes by acting as a sponge of miR-124a to modulate CDK2 and MCP-1 expression. Furthermore, the agonists of LXR inhibited lncRNA-H19-mediated miR-124a-CDK2/MCP-1 signalling pathway in synoviocytes. The ‘lncRNA-H19-miR-124a-CDK2/MCP-1’ axis plays an important role in LXR anti-arthritis. Conclusion Regulation of the miR-124a-CDK2/MCP-1 pathway by lncRNA-H19 plays a crucial role in the proliferation of FLS. Targeting this axis has therapeutic potential in the treatment of RA and may represent a novel strategy for RA treatment.

Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by synovial hyperplasia and local inflammatory cell infiltration, 1,2 which eventually leads to cartilage destruction, bone erosion, and joint dysfunction. 3,4 Although the pathogenesis of RA remains to be elucidated, fibroblast-like synoviocytes (FLSs) are the effector cells of RA and play a crucial role in the inflammatory process. [5][6][7] In the inflammatory process of RA, FLS acquires the ability of excessive proliferation, secretion of pro-inflammatory cytokines, migration, and invasion, which can further aggravate RA. 8,9 However, current therapeutic strategies and drugs cannot target the activated FLS. 10 Therefore, clarifying the underlying mechanisms of abnormally activated FLS will help to explore novel therapeutic targets and approaches in RA.Dual-specificity phosphatase 5 (DUSP5), a member of the DUSP subfamily, can directly dephosphorylate extracellular signal-regulated kinases 1 and 2 (hereinafter referred to as ERK) 11 and is an intrinsic negative regulator of ERK. 12 It has been implicated as a major modulator of critical signaling pathways in several diseases. Previous studies confirmed that DUSP5 is a direct target gene of p53 and has tumor-suppressive functions in several types of cancer. 13,14 Recently,

Dual-specificity phosphatase 5 (DUSP5) is a novel anti-inflammatory modulator in many inflammatory diseases. However, the role of DUSP5 in the fibroblast-like synoviocytes (FLS) of Rheumatoid arthritis (RA) remains unknown. In this study, we aimed to explore the biological function and regulation of DUSP5 in FLS. We found that lower DUSP5 expression levels were detected in collagen-induced arthritis (CIA) and synoviocytes MH7A. Overexpression of DUSP5 markedly decreased the proliferation, migration, and invasion of MH7A, which correlated with suppressing the phosphorylation of ERK. Moreover, DUSP5 was identified as a novel target gene of miR-216a-3p, which is upregulated in FLS. Therefore, DUSP5 expression was negatively regulated by miR-216a-3p, and the effect of DUSP5 overexpression on FLS was reversed by miR-216a-3p mimics. Overall, our study demonstrates that DUSP5 is a miR-216a-3p target gene and its anti-inflammatory function in FLS via inactivation of ERK. These results revealed that the miR-216a-3p/DUSP5 pathway may play a crucial role in the malignant behavior of FLS, which may serve as a new target for the treatment of RA.