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AB0113 Secreted frizzled-related protein 5 inhibits expression of pro-inflammatory mediators by down-regulation of JNK in rheumatoid arthritis
  1. Y.-J. Kwon,
  2. T.-Y. Kim,
  3. S.-W. Lee,
  4. Y.-B. Park,
  5. S.-K. Lee,
  6. M.-C. Park
  1. Division of Rheumatology, Yonsei University College of Medicine, Seoul, Korea, Republic Of

Abstract

Background The adipokines are linked not only to metabolic regulation, but also to immune responses. Secreted frizzled-related protein 5 (Sfrp5) is a new adipokine with anti-inflammatory properties that has beneficial effects on metabolic dysfunction. Sfrp5 acts as a decoy receptor that binds and sequesters Wnt5a in the extracellular environment, thus preventing activation of frizzled and attenuating non-canonical Wnt signaling. Consequentially, c-Jun N-terminal kinase (JNK), a downstream target of non-canonical Wnt signaling, is also inhibited.

Objectives This study was performed to investigate the mRNA expression of Sfrp5 in peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocyte (FLS) of patients with rheumatoid arthritis (RA) compared to osteoarthritis (OA), and to determine the effects of Sfrp5 on pro-inflammatory gene expressions in rheumatoid FLS.

Methods The mRNA expression of Sfrp5 was measured in PBMCs and FLS of patients with RA or OA by real-time quantitative RT-PCR. Synovial tissues were obtained from patients with RA during total knee replacement surgery, and then FLS were isolated and cultured. Adenovirus containing Sfrp5 transcript was constructed and delivered into rheumatoid FLS. The mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (CCL-2), cyclo-oxygenase2 (COX-2), and matrix metalloproteinase-9 (MMP-9) were determined using quantitative real-time PCR in FLS expressing adenoviral Sfrp5 as well as in control-treated FLS. Western blot analysis was performed to assess MKK4, MKK-7, ATF-2, c-Jun and JNK activity from both treatment groups.

Results Sfrp5 mRNA expression in PMBCs and FLS from patients with RA was significantly decreased than OA. Ectopic expression of Sfrp5 in rheumatoid FLS reduced the mRNA expressions of TNF-α, IL-1β, IL-6, CCL-2, COX-2 and MMP-9 as compared with control-treated FLS. The activity of MKK4, MKK-7, ATF-2, c-Jun and JNK were diminished in FLS receiving forced expression of Sfrp5.

Conclusions Increased levels of Sfrp5 suppressed various pro-inflammatory gene expressions via modulation of JNK. These results suggest that Sfrp5may be a strategy for treatment of patients with RA.

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  2. Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, et al. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 2007;6:386–97.

  3. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature 2002;420:333–6.

Disclosure of Interest None Declared

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