Background/Purpose: Decoy receptor 3 (DcR3) is a secreted decoy tumor necrosis factor receptor and competitively binds and inhibits the TNF family including Fas-ligand, LIGHT, and TL1A. We previously reported that DcR3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated by TNFα protects the cells from Fas-induced apoptosis [1]. We recently reported that DcR3 binds to TL1A expressed on RA-FLS resulting in the negative regulation of cell proliferation induced by inflammatory cytokines [2]. Further, we newly revealed the gene expression profiles in RA-FLS regulated by DcR3 by using microarray data analysis [3] and the possible involvement of tryptophan hydroxylase 1 down-regulated [4], interleukin 12B up-regulated by DcR3 [5] and centrosomal protein 70kDa [6] in the pathogenesis of RA. The profiles indicated that Cadherin 2/type 1/N-cadherin (CDH2) was up-regulated by DcR3 (fold change 1.93) [3]. CDH2 has been reported to be associated with cell attachment and migration [7], osteoblast differentiation [8], and the proliferation of RA-FLS [9]. The hemophilic interaction of CDH2 suppresses the proliferation of RA-FLS through increasing the P27^Kip1 that inhibit cell-cycle progression [9]. In this study, we investigated the significance of DcR3 regulation of CDH2 for RA-FLS.

Methods: Before the quantification of relative expression levels of CDH2 mRNA by real-time polymerase chain reaction (real-time PCR), RA-FLS were stimulated with various concentration of DcR3-Fc or 1,000 ng/ml IgG1 as a control, or left untreated in serum-free Opti-MEM® for 12 h. Anti-CDH2 antibody was applied to frozen sections of synovial tissues from patients with RA or OA for overnight. After that, the expression of CDH2 protein was evaluated by immunohistochemical analysis.

Results: Real-time PCR demonstrated that DcR3-Fc significantly increased the expression of CDH2 mRNA in RA-FLS. Immunohistochemistry revealed that CDH2 was expressed more in the sublining layer of rheumatoid synovium than OA synovium.

Conclusion: In the gene expression profiles, we focused on CDH2 as the gene was highly up-regulated and belonged to major functional clustering categories; protein complex assembly, cell motility, regulation of transcription, cell membrane and glycosylation. In this study, we showed that the expression of CDH2 mRNA in RA-FLS was induced by DcR3 and that CDH2 was increased in the sublining layer of rheumatoid synovium. Considering the fact that CDH2 inhibits RA-FLS proliferation, the induction in CDH2 expression by DcR3 signaling may control the hyperplasia of RA synovium.

References: 1. Hayashi S. et al., Arthritis Rheum. 2007;56:1067-1074,

2. Takahashi M. et al., Int J Mol Med. 2011;28:423-427,

3. Fukuda K. et al., Int J Mol Med. 2013;32:910-916,

4. Maeda T. et al., Mol Med Rep. 2015;12:5191-5196,

5. Fukuda K. et al., Mol Med Rep. 2016;13:3647-3652,

6. Fukuda K. et al., Mod Rheumatol. in press

7. Akitaya T. et al., Dev Dyn. 1992;194:12-20.

8. Marie P, J Cell Physiol 2002;190:297-305.

9. Nonomura Y. et al., J Rheumatol. 2009;36:698-705.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/decoy-receptor-3-up-regulates-cadherin-2-in-rheumatoid-synovial-fibroblasts/