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Sprouty2 Inhibits Migration and Invasion of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis by Down-regulating ATF2 Expression and Phosphorylation

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Abstract

Activating transcription factor 2(ATF2), a transcription factor belonging to the AP-1 family, plays an important role in inflammation. However, its biological functions and underlying molecular mechanisms in rheumatoid arthritis (RA) remain unclear. Western blot and immunohistochemistry were used to identify the expression of ATF2 and Sprouty2(SPRY2) in RA synovial tissues. SW982 cells were stimulated by TNF-α to establish an in vitro RA fibroblast-like synoviocyte (RA-FLS) model. Transwell and monolayer wound-healing were used to detect cell migration and invasion. RNA interference (si-ATF2) and adenovirus vector (Ad-SPRY2) methods were employed to manipulate ATF2 or SPRY2 expression in SW982 cells. The protein expression and phosphorylation levels in SW982 cells were evaluated by western blot. ATF2 expression and phosphorylation were upregulated in the RA synovial tissues. In RA-FLS model, ATF2 expression and phosphorylation were increased in a time-dependent manner. ATF2 knockdown inhibited the migration and invasion of RA-FLS model, reducing the inflammatory factors, which was consistent with the influence on cell behaviors caused by SPRY2 overexpression. Moreover, SPRY2 overexpression inhibited the TNF-α-induced phosphorylation of ERK and ATF2 in SW982 cells. The high expression and phosphorylation of ATF2 promoted migration and invasion of RA-FLSs. SPRY2 might inhibited the inflammatory responses of RA-FLSs via suppressing ERK-ATF2 pathway.

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Funding

This work was supported by the National Natural Science Foundation of China (81702216), Scientific Research Project of “333 Project” in Jiangsu Province (BRA2018224), Nantong Science and Technology Project (JC2019031), Scientific Research Project of Health Commission of Jiangsu Province (H2018035).

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  1. **ng Zhang and Dongmei Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, The Second Affiliated Hospital of Nantong University, No. 6 Haier Lane North Road, Nantong, 226001, Jiangsu Province, People’s Republic of China

    **ng Zhang, Qinyu Wang, **aofeng Guo, Jiajia Chen, Jiawei Jiang, Wei Liu, Guofeng Bao & Zhiming Cui

  2. Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China

    Dongmei Zhang & Mengmeng Li

  3. Department of Rheumatology, The Second Affiliated Hospital of Nantong University, 226001, Jiangsu Province, Nantong, People’s Republic of China

    Yingying Gao

  4. The Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China

    Qi Zhang

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Fig. S1

SW982 cells were transfected with si-ATF2#1, and si-Ctrl was used as a negative control. a Western blot confirmed that inhibition of ATF2 reduced the protein expression of MMP-13 and IL-1β in SW982 cells stimulated by TNF-α (10ng/ml). b ELISA indicated that ATF2 inhibition can effectively reduce the level of IL-6 in SW982 cell supernatant, with or without TNF-α stimulation. c The monolayer wound-healing assay was used to access the migration ability of SW982 cells. d The invasion assay was carried out in a Matrigel basement membrane matrix chamber. All values represent the mean ± SD, *P<0.05 vs control. (JPG 2.91 mb)

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Zhang, X., Zhang, D., Wang, Q. et al. Sprouty2 Inhibits Migration and Invasion of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis by Down-regulating ATF2 Expression and Phosphorylation. Inflammation 44, 91–103 (2021). https://doi.org/10.1007/s10753-020-01311-z

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