Abstract
Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.
Highlights
Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by persistent synovitis, systemic inflammation, and joint destruction [1, 2]
WAKMAR2 silencing with the presence of LLDT-8 recovered the beneficial effects of miR-4478 overexpression on proliferation and invasion of RA Fibroblast-like synoviocytes (FLS), expression of PCNA and Cyclin D1, as well as the levels of matrix metalloproteinases-3 (MMP-3), IL-1, and IL-6 (Figures 7B–F, Supplementary Figures 4B,E).These results demonstrated the essential role of LLDT-8/WAKMAR2/miR-4478/E2F1/p53 axis in RA FLS (Figure 8)
LLDT-8 prevents collagen-induced arthritis via inhibiting OPG/RANK/RANKL signaling in osteoclastogenesis and IFNgamma signaling in T cells [12, 13]
Summary
Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by persistent synovitis, systemic inflammation, and joint destruction [1, 2]. The synovium is transformed into a hyperplastic tissue in patients with RA [3]. Fibroblast-like synoviocytes (FLS) are the most common cells at the pannus-cartilage junction and serve a major role in the hyperplastic process of synovium [4]. FLS exhibit unique features with aggressive and invasive properties in RA, which are tumor-like phenotypes [5]. FLS invade joint cartilage and contribute to joint destruction through the production of pro-inflammatory cytokines, chemokines, and matrix-degrading molecules [6]. Targeting FLS is emerging as an attractive therapeutic approach in the RA treatment [3]
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