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Transforming growth factor β1 promotes fibroblast-like synoviocytes migration and invasion via TGF-β1/Smad signaling in rheumatoid arthritis

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Abstract

Migration and invasion are important characteristics of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), which are involved in joint damage and contribute to rheumatoid arthritis (RA) pathology. However, the underlying mechanisms remain unclear. Because epithelial–mesenchymal transition (EMT) is a key mechanism related to migration and invasion in cancer cells, we investigated the relationship between EMT and RA-FLSs and explored whether the transforming growth factor β1 (TGF-β1)/Smad signaling pathway is involved. In vivo, fibroblast-like synoviocytes (FLSs) were isolated from the synovium of RA or osteoarthritis (OA) patients and cultured for 4–8 passages. EMT markers were detected by immunofluorescence and Western blotting. RA-FLSs were treated with TGF-β1 or Smad2/3 small interfering RNA (siRNA), EMT markers were detected, and migration and invasion were assessed by Transwell assays. EMT markers could be detected in FLSs; when compared with osteoarthritis fibroblast-like synoviocytes (OA-FLSs), E-cadherin and vimentin decreased, while N-cadherin and α-smooth muscle actin (α-SMA) increased in RA-FLSs. Furthermore, TGF-β1 enhanced migration and invasion by inducing EMT via activating Smad2/3 in RA-FLSs. Phosphorylation of Smad2/3 was accompanied by degradation of Smad3. Silencing Smad2/3 blocked EMT and inhibited the migration and invasion induced by TGF-β1. Matrix metalloproteinase 9 (MMP9) and vimentin were not affected when cells were treated with TGF-β1 or Smad2/3 siRNA. The TGF-β1/Smad signaling pathway is involved in EMT and contributes to migration and invasion in RA-FLSs. Interestingly, vimentin decreased in RA-FLSs, but there is no correlation between vimentin and TGF-β1/Smad signaling pathway. Thus, further research on vimentin should be conducted.

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Acknowledgements

The present study was supported by National Natural Science Foundation of China (Grant Nos. 81771747, 81801624) and Natural Science Foundation of Guangdong Province (Grant No. 2017A030313475).

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Author notes

  1. DingJi Zhu, JinJun Zhao, AiJu Lou, Qin Huang and QingQing OuYang contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Northern 1838th Guangzhou Avenue, Guangzhou, 510515, Guangdong, People’s Republic of China

    DingJi Zhu, JinJun Zhao, AiJu Lou, Qin Huang, QingQing OuYang, JunQing Zhu, MeiDa Fan, Hao Ren & Min Yang

  2. Department of Rheumatology and Immunology, Liwan Hospital of The Third Affiliated Hospital, Guangzhou Medical University, Guangdong, China

    AiJu Lou

  3. Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat Sen University, Guangzhou, Guangdong, China

    YingQiong He

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  1. DingJi Zhu
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Zhu, D., Zhao, J., Lou, A. et al. Transforming growth factor β1 promotes fibroblast-like synoviocytes migration and invasion via TGF-β1/Smad signaling in rheumatoid arthritis. Mol Cell Biochem 459, 141–150 (2019). https://doi.org/10.1007/s11010-019-03557-0

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