ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1463

Dickkopf-1 Perpetuated Synovial Fibroblast Activation and Synovial Angiogenesis in Rheumatoid Arthritis

Li Zheng1, Fanlei Hu2, Yingni Li1, Lianjie Shi2, Xiaoxu Ma1, Xuewu Zhang3 and Zhanguo Li4, 1Peking University People's Hospital, Beijing, China, 2Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China, 311 South Street, XiZhiMen , We, Peking University People's Hospital, Beijing, China, 4Rheum/Immunology, Peking University People's Hospital, Beijing, China

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

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.

Disclosure:

L. Zheng,
None;

F. Hu,
None;

Y. Li,
None;

L. Shi,
None;

X. Ma,
None;

X. Zhang,
None;

Z. Li,
None.

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