SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Abstract

BackgroundTissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets.ObjectiveThe present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction in vitro.Materials and MethodsThe levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points.ResultsOur data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1β, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5.ConclusionWnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.

The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis

“…It has been shown that RA SF-FLS release multiple inflammatory cytokines dominated by CCL2 and IL6 without exogenous stimulation (19). This corroborates the findings of previous data showing that RA SF-FLS secrete IL6, IL8, IL1b and CCL2 (17,34). In addition, RA FLS from the intimal lining have been considered primary sources of IL6, as shown by in situ hybridization and immunohistochemistry studies (6).…”

“…SF-FLS from patients with RA display multiple changes in cell morphology during culture (17,18,34). Under light microscopy, SF-FLS appear elongated with an irregular stellate cell shape during the first few days of culture (16,17).…”

“…Additionally, SF-FLS and fibrocytes from patients with RA express the Wingless (Wnt) receptors: Frizzled (Fzd) 4, Fzd5, Ror2, Ryk and the low density lipoprotein receptor-related protein 5 (LRP5). These receptors play an important role in FLS-mediated inflammatory response and cell migration (34).…”

Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments

“…Furthermore, it also produces Wnt5a, which promotes osteoclast differentiation [ 131 , 132 ]. The expression of Wnt5a in FLS induces inflammatory cytokines [ 133 , 134 , 135 , 136 ], which activate FLS itself. Recent studies using single-cell analysis have shown that cells in the blood, such as macrophages and lymphocytes, are main sources of TNF-α in the synovium of patients with RA [ 137 ].…”

SFRP1 Negatively Modulates Pyroptosis of Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis: A Review

“…Fibroblast-like synoviocytes (FLS) is a special group of cells in the synovial tissue. During the pathogenesis of RA, FLS show high proliferation, high invasiveness, and tumor-like changes, which play an important role in the development of RA ( 3 , 4 ). Previous studies have shown that apoptosis and autophagy in FLS are closely related to the development of RA ( 5 , 6 ).…”