Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation
Yaoyao Zou, Siqi Xu, Youjun Xiao, Qian Qiu, Maohua Shi, Jingnan Wang, Liuqin Liang, Zhongping Zhan, Xiuyan Yang, Nancy Olsen, Song Guo Zheng, Hanshi Xu
Yaoyao Zou, Siqi Xu, Youjun Xiao, Qian Qiu, Maohua Shi, Jingnan Wang, Liuqin Liang, Zhongping Zhan, Xiuyan Yang, Nancy Olsen, Song Guo Zheng, Hanshi Xu
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Research Article Immunology

Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation

Abstract

Fibroblast-like synoviocytes (FLSs) are critical to synovial aggression and joint destruction in rheumatoid arthritis (RA). The role of long noncoding RNAs (lncRNAs) in RA is largely unknown. Here, we identified a lncRNA, LERFS (lowly expressed in rheumatoid fibroblast-like synoviocytes), that negatively regulates the migration, invasion, and proliferation of FLSs through interaction with heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Under healthy conditions, by binding to the mRNA of RhoA, Rac1, and CDC42 — the small GTPase proteins that control the motility and proliferation of FLSs — the LERFS–hnRNP Q complex decreased the stability or translation of target mRNAs and downregulated their protein levels. But in RA FLSs, decreased LERFS levels induced a reduction of the LERFS–hnRNP Q complex, which reduced the binding of hnRNP Q to target mRNA and therefore increased the stability or translation of target mRNA. These findings suggest that a decrease in synovial LERFS may contribute to synovial aggression and joint destruction in RA and that targeting the lncRNA LERFS may have therapeutic potential in patients with RA.

Authors

Yaoyao Zou, Siqi Xu, Youjun Xiao, Qian Qiu, Maohua Shi, Jingnan Wang, Liuqin Liang, Zhongping Zhan, Xiuyan Yang, Nancy Olsen, Song Guo Zheng, Hanshi Xu

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Figure 2

Inhibitory effects of LERFS overexpression on RA FLS migration and invasion.

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Inhibitory effects of LERFS overexpression on RA FLS migration and invas...
(A and B) Chemotaxic migration of RA FLSs (A) or HC FLSs (B) was evaluated using a Transwell assay. Representative images (original magnification, ×100) are shown. Graphs indicate the relative migration rates. (C and D) The migration of RA FLSs (C) or HC FLSs (D) was analyzed using a wound-healing assay. Representative images are shown (original magnification, ×50). The relative migration rate represents the number of migrated cells normalized to the vector control. (E and F) In vitro invasion was determined using inserts coated with Matrigel Basement Membrane Matrix. The relative invasion rate was calculated by counting invaded cells and then normalized to the vector control. Representative images (original magnification, ×100) are shown. Graphs indicate the relative invasion rates. (G) LERFS overexpression impaired the formation of pseudopodium in RA FLSs. RA FLSs were wounded and stimulated with PDGF-BB (10 ng/ml) for 4 hours. Representative images are shown. Original magnification, ×400 (top); ×1,000 (bottom). Red arrow indicates lamellipodia formation; yellow arrow indicates filopodia formation. Graph indicates the number of RA FLSs with positive lamellipodia or filopodia. (H and I) Images show that LERFS knockdown promoted HC FLS migration (H) and invasion (I). Original magnification, ×100. Graphs indicate the relative migration (H) and invasion (I) rates. (J) Effect of LERFS overexpression on in vivo migration of RA FLSs. Representative images are shown (original magnification, ×400); red arrows indicate human FLSs. Graph indicates the number of migrated human FLSs stained with anti-human class I HLA antibody. (K) Effect of LERFS overexpression on the invasion of RA FLSs into human cartilage implants transferred under the skin of SCID mice. Arrows indicate RA FLS invasion into cartilage (Ca). Original magnification, ×200 (left); ×400 right (enlarged). Graph indicates the invasion scores. Data are shown as the mean ± SEM of 5 independent experiments involving 5 different RA patients or HCs. *P < 0.05, **P < 0.01, and ***P < 0.001 versus vector control, by Student’s t test.