Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Background/Purpose . Dkk-1, a master regulator of joint remodeling, is elevated and leads to bone resorption in patients with RA. This study aimed to investigate the contribution of Dkk-1 to synovial inflammation and synovial fibroblasts-mediated angiogenesis in RA.
Methods . Dkk-1 concentration in synovial fluids from RA and osteoarthritis (OA) patients was evaluated by ELISA. The expression of Dkk-1 in RA synovial fibroblasts (RASF) and OASF was compared by real-time PCR and ELISA. RASF were stimulated with different pro-inflammatory factors and the expression of Dkk-1 was determined by real-time PCR and ELISA. The expression of angiogenic factors (MCP-1, SDF-1, VEGF, ADAM-10 and CD147), pro-inflammatory cytokines (TNF-α, IL-6, IL-8 and IL-1β), and MMPs (MMP-1, MMP-3 and MMP-9) in RASF was determined by real-time PCR when DKK-1 was knocked down or overexpressed. Meanwhile, the levels of MCP-1, IL-6, IL-8, and MMP-3 in the cell culture supernatants were determined by ELISA. The effects of Dkk-1 on the MAPK signaling pathway was evaluated by Western blot when it was silenced. Matrigel tube formation assay was employed to reveal the direct and indirect effect of Dkk-1 on synovial angiogenesis.
Results . Levels of Dkk-1 in synovial fluids and synovial fibroblasts were elevated in RA patients. The secretion of Dkk-1 was accelerated by various pro-inflammatory cytokines in RASF, including TNF-α,IL-6,IL-17,INF-γand IL-1β. Dkk-1 stimulated the production of potent angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF, while silencing Dkk-1 expression suppressed such factor expression. Silencing Dkk-1 in RASF dampened its mediated capillary tube organization both in direct and indirect manners, accompanied with restrained ERK, JNK, and p38 signaling pathway activation.
Conclusion . Dkk-1 exacerbated synovial fibroblasts-mediated inflammation, cartilage erosion, and angiogenesis in RA. Targeting Dkk-1 might provide novel therapeutic strategy for overcoming the persistent disease.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/dickkopf-1-perpetuated-synovial-fibroblast-activation-and-synovial-angiogenesis-in-rheumatoid-arthritis/