title: Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Correspondence to Christoph J Wruck, Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany. cwruck@ukaachen.de
authors.forename: Christoph Jan
authors.initials: CJ
authors.lastname: Wruck
authors.forename: Athanassios
authors.initials: A
authors.lastname: Fragoulis
authors.forename: Agata
authors.initials: A
authors.lastname: Gurzynski
authors.forename: Lars-Ove
authors.initials: LO
authors.lastname: Brandenburg
authors.forename: Yuet Wai
authors.initials: YW
authors.lastname: Kan
authors.forename: Kaimin
authors.initials: K
authors.lastname: Chan
authors.forename: Joachim
authors.initials: J
authors.lastname: Hassenpflug
authors.forename: Sandra
authors.initials: S
authors.lastname: Freitag-Wolf
authors.forename: Deike
authors.initials: D
authors.lastname: Varoga
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lippross
authors.forename: Thomas
authors.initials: T
authors.lastname: Pufe
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002358:Cartilage, Articular / Q000473:pathology / Q000503:physiopathology; D005598:Fractures, Spontaneous / Q000209:etiology / Q000473:pathology; D015870:Gene Expression; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D013879:Thioredoxins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D013879:Thioredoxins; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase