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Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice
  1. Christoph Jan Wruck1,
  2. Athanassios Fragoulis1,
  3. Agata Gurzynski2,
  4. Lars-Ove Brandenburg1,
  5. Yuet Wai Kan4,
  6. Kaimin Chan5,
  7. Joachim Hassenpflug6,
  8. Sandra Freitag-Wolf7,
  9. Deike Varoga3,
  10. Sebastian Lippross3,
  11. Thomas Pufe1
  1. 1Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
  2. 2Ear, Nose and Throat Department, UKSH Campus Kiel, Kiel, Germany
  3. 3Department of Trauma Surgery, UKSH Campus Kiel, Kiel, Germany
  4. 4Department of Laboratory Medicine, University of California, San Francisco, USA
  5. 5Department of Medicine, University of Hong Kong, Hong Kong
  6. 6Department of Orthopaedic Surgery, UKSH Campus Kiel, Kiel, Germany
  7. 7Institute of Medical Informatics and Statistics, UKSH Campus Kiel, Kiel, Germany
  1. Correspondence to Christoph J Wruck, Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany; cwruck{at}


Objectives Increasing evidence suggests that oxidative stress may play a key role in joint destruction due to rheumatoid arthritis (RA). The aim of this study was to elucidate the role of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that maintains the cellular defence against oxidative stress, in RA.

Methods The activation status of Nrf2 was assessed in synovial tissue from patients with RA using immunohistochemistry. Antibody-induced arthritis (AIA) was induced in Nrf2-knockout and Nrf2-wild-type control mice. The severity of cartilage destruction was evaluated using a damage score. The extent of oxidative stress, the activation state of Nrf2 and the expression level of Nrf2 target genes were analysed by immunhistological staining. The expression of vascular endothelial growth factor (VEGF)-A was examined on mRNA and protein using the Luminex technique. A Xenogen imaging system was used to measure Nrf2 activity in an antioxidant response element-luciferase transgenic mouse during AIA.

Results Nrf2 was activated in the joints of arthritic mice and of patients with RA. Nrf2-knockout mice had more severe cartilage injuries and more oxidative damage, and the expression of Nrf2 target genes was enhanced in Nrf2-wild-type but not in knockout mice during AIA. Both VEGF-A mRNA and protein expression was upregulated in Nrf2-knockout mice during AIA. An unexpected finding was the number of spontaneously fractured bones in Nrf2-knockout mice with AIA.

Conclusion These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.

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  • CJW, AF, AG, DV, SL and TP contributed equally to the work.

  • Funding This research project received funding from the ‘Deutsche Forschungsgemeinschaft’ Pu 214/3-2, Pu 214/4-2 and Pu 214/5-2 and SFB617 and was also supported by the START-Program of the Faculty of Medicine, RWTH Aachen University.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the institutional review board.

  • Provenance and peer review Not commissioned; externally peer reviewed.