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

  • DingJi Zhu
  • JinJun Zhao
  • AiJu Lou
  • Qin Huang
  • QingQing OuYang
  • JunQing Zhu
  • MeiDa Fan
  • YingQiong He
  • Hao RenEmail author
  • Min YangEmail author


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.


Rheumatoid arthritis Epithelial–mesenchymal transition Transforming growth factor β1 Migration Invasion 



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).

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflicts of interest exist.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Southern Medical University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Rheumatology and Immunology, Nanfang HospitalSouthern Medical UniversityGuangzhouPeople’s Republic of China
  2. 2.Department of Rheumatology and ImmunologyLiwan Hospital of The Third Affiliated Hospital, Guangzhou Medical UniversityGuangdongChina
  3. 3.Department of Ultrasound, The Fifth Affiliated HospitalSun Yat Sen UniversityGuangzhouChina

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