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Objective: Dickkopf-1 (Dkk-1), a regulatory molecule of the Wnt pathway, is elevated and leads to bone resorption in patients with RA. This study is aimed to investigate the contribution of Dkk-1 to synovial inflammation and synovial fibroblast-mediated angiogenesis in RA., Methods: The expression of Dkk-1 in RA synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF) was detected by real-time PCR and ELISA, respectively. RASF were stimulated with different pro-inflammatory factors. The expression of angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was analyzed by real-time PCR when Dkk-1 was inhibited or overexpressed. Meanwhile, the concentrations of MCP-1, IL-6, IL-8, and MMP-3 in the cell culture supernatant were assessed by ELISA. The effects of Dkk-1 on the MAPK signaling pathway were evaluated by western blot. Matrigel tube formation assay was employed to reveal the direct and indirect effects of Dkk-1 on synovial angiogenesis., Results: Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression in RASF. The production of potent angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was elevated, whereas the reverse results were found in the inhibitor groups. Silenced Dkk-1expression in RASF dampened capillary tube organization in both direct and indirect manners, resulting in restrained ERK, JNK, and p38 signaling pathway activation., Conclusion: We concluded that Dkk-1 exacerbated the inflammation, cartilage erosion, and angiogenesis mediated by synovial fibroblasts in RA. Modulation of DKK-1 expression may facilitate development of novel strategies to control RA. Key points • Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. • Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression. • Silenced Dkk-1expression in RASF dampened capillary tube organization., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objective: As an important feature of rheumatoid arthritis (RA), an excessive amount of pro-inflammatory cytokines in RA synovial lesions induces the proliferation of synovial fibroblasts, cartilage erosion and systemic inflammatory immune response. Wnt inhibitor, Dkk-1, contributes to joint remodeling. This study was conducted to explore the role of Dkk-1 in the regulation of pro-inflammatory cytokine secretion., Methods: Rheumatoid arthritis synovial fibroblasts (RASF) were cultured from surgical synovial specimens and utilized at passages 4-8. For Dkk-1 silencing assay, Dkk-1-specific siRNA and control scrambled siRNA were transfected into RASF respectively. For Dkk-1 over-expression assay, Dkk-1 plasmid and control vector were transfected into RASFs respectively. Production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8), were measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) at pre- and post-transfection respectively. Differences between various groups were evaluated by Wilcoxon signed-rank test., Results: After a treatment of Dkk-1-specific siRNA, RASF exhibited decreased production of pro-inflammatory cytokines in association with down-regulated Dkk-1 levels while Dkk-1 over-expression could up-regulate the production of pro-inflammatory cytokines. The effects were marked when RAFS was activated by TNF-α and IL-1β after transfection., Conclusion: Dkk-1 promotes the production of pro-inflammatory cytokines in RASF so as to exacerbate synovitis of RA. And targeting Dkk-1 may provide a novel therapeutic strategy for RA.

Objective: Leukocyte immunoglobulin-like receptor A3 belongs to a family of receptors with inhibitory or activating functions. Since Caucasian individuals lacking LILRA3 have been found to be susceptible to multiple sclerosis and Sjögren's syndrome, we undertook this study to examine whether LILRA3 deletion is a novel genetic risk factor for rheumatoid arthritis (RA) (another autoimmune disease), whether there are sex-specific effects, and whether LILRA3 influences the subtype and severity of RA., Methods: The LILRA3 deletion and its tagging single-nucleotide polymorphism rs103294 were genotyped in a Northern Han Chinese cohort (N-Han) (1,618 cases and 1,658 controls) and a Southern Han Chinese cohort (S-Han) (575 cases and 549 controls). Association analyses were performed on the complete data set and subsets. The effect of the nondeleted (functional) LILRA3 allele on radiographic severity and LILRA3 expression was evaluated., Results: In the N-Han discovery cohort, we unexpectedly observed a higher frequency of the functional LILRA3 in RA patients compared with healthy individuals (10.1% versus 6.3%; P = 4.01 × 10(-5) , odds ratio [OR] 1.92). The association was replicated in the S-Han cohort and confirmed by meta-analysis (P = 5.63 × 10(-6) , OR 1.83). Functional LILRA3 conferred greater risk for RA in males (P = 1.09 × 10(-6) , OR 4.47), and was specifically associated with anti-citrullinated protein antibody (ACPA)-positive RA (P = 3.05 × 10(-4) , OR 1.75). Furthermore, functional LILRA3 was associated with higher radiographic scores in ACPA-positive patients with early RA (P = 9.70 × 10(-3) ) and higher LILRA3 messenger RNA levels (P = 3.31 × 10(-8) )., Conclusion: Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for RA, especially in males. It appears to highly predispose to ACPA-positive RA and confers an increased risk of disease severity in patients with early RA., (Copyright © 2014 by the American College of Rheumatology.)

Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease.