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PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial–mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis

Molecular and Cellular Biochemistry volume 372, pages 221–231 (2013)Cite this article

Abstract

Migration and invasion of fibroblast-like synoviocytes (FLSs) are critical in the pathogenesis of rheumatoid arthritis (RA). Hypoxic conditions are present in RA joints, and hypoxia has been extensively studied in angiogenesis and inflammation. However, its effect on the migration and invasion of RA-FLSs remains unknown. In this study, we observed that RA-FLSs exposed to hypoxic conditions experienced epithelial–mesenchymal transition (EMT), with increased cell migration and invasion. We demonstrated that hypoxia-induced EMT was accompanied by increased hypoxia-inducible factor (HIF)-1α expression and activation of Akt. After knockdown or inhibition of HIF-1α in hypoxia by small interfering RNA or genistein (Gen) treatment, the EMT transformation and invasion ability of FLSs were regained. HIF-1α could be blocked by phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, indicating that HIF-1α activation was regulated by the PI3K/Akt pathway. Administration of LY294002 (20 mg/kg, intra-peritoneally) twice weekly and Gen (25 mg/kg, by gavage) daily for 3 weeks from day 20 after primary immunization in a collagen-induced arthritis rat model, markedly alleviated the clinical signs, radiology progression, synovial hyperplasia, and inflammatory cells infiltration of joints. Thus, results of this study suggest that activation of the PI3K/Akt/HIF-1α pathway plays a pivotal role in mediating hypoxia-induced EMT transformation and invasion of RA-FLSs under hypoxia.

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Acknowledgments

This research was sponsored by the Graduate Student Research and Innovation Program of Jiangsu Province (No.CXZZ11-0998).

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Affiliations

  1. Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China

    Guo-Qing Li, Yu Zhang & Dan Liu

  2. Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China

    Ya-Yun Qian, Hua Zhang & Yan-Qing Liu

  3. Department of Physiology, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Shi-Yu Guo, Masataka Sunagawa & Tadashi Hisamitsu

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  1. Guo-Qing Li
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Li, GQ., Zhang, Y., Liu, D. et al. PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial–mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis. Mol Cell Biochem 372, 221–231 (2013). https://doi.org/10.1007/s11010-012-1463-z

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  • DOI: https://doi.org/10.1007/s11010-012-1463-z

Keywords

  • Hypoxia
  • Epithelial–mesenchymal transition
  • Fibroblast-like synoviocytes
  • HIF-1α
  • PI3K/Akt
  • Rheumatoid arthritis