Background/Purpose:

Secreted frizzled-related protein 5 (Sfrp5) is a novel adipokine that has beneficial effects on metabolic dysfunction by controlling inflammatory cells within adipose tissue. Sfrp5 acts as a soluble modulator that binds and sequesters Wnt proteins in the extracellular space and that prevents the 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 inhibited. The purposes of this study are to determine the expression of Sfrp5 in fibroblast-like synoviocyte (FLS) from rheumatoid arthritis (RA) patients and to investigate the correlation between the expression levels of Sfrp5 and that of pro-inflammatory genes in RA FLS.  

Methods:

FLS were isolated and cultured from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee replacement surgery. The mRNA expressions of Sfrp5 in peripheral blood mononuclear cells (PBMCs) and FLS from patients with RA or OA were determined using real-time quantitative RT-PCR. Adenovirus containing Sfrp5 transcript was constructed and delivered into RA FLS to strengthen Sfrp5 expression, then, Sfrp5 RNAi plasmid was transfected to abrogate Sfrp5 expression in RA FLS. The mRNA expressions of TNF-α, IL-1β, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 were also determined using quantitative real-time PCR and western blot analysis was performed to assess MKK4, MKK-7, ATF-2, c-Jun and JNK activity in RA FLS.

Results:

Expression of Sfrp5 mRNA in PMBCs from RA patients was significantly decreased compared to those from OA patients, and this decrease was more accentuated in RA FLS compared to OA FLS (more than 10-fold in OA FLS). The mRNA expressions of TNF-α, IL-1β, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 were remarkably increased in Sfrp5 RNAi plasmid-transfected RA FLS, compared to non-silencing RNAi plasmid-transfected RA FLS. However, adenoviral vectors encoding Sfrp5 significantly reduced the mRNA levels of TNF-α, IL-1β, IL-6, CCL-2, CCL-7, COX-2 and MMP-9 as compared with control vector. The activity of MKK4, MKK-7, ATF-2, c-Jun and JNK were up-regulated in RA FLS with no Sfrp5 expression by Sfrp5 RNAi plasmid; and were down-regulated with strong Sfrp5 expression by adenoviral vectors encoding Sfrp5.

Conclusion:

Sfrp5 suppressed various pro-inflammatory gene expressions via modulation of JNK. These findings suggest that Sfrp5 may have a certain role in RA pathogenesis and have an anti-inflammatory effect.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/secreted-frizzled-related-protein-5-exerts-the-anti-inflammatory-role-in-rheumatoid-arthritis-via-down-regulation-of-c-jun-n-terminal-kinase/