Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease

Antioxid Redox Signal. 2011 Aug 15;15(4):889-901. doi: 10.1089/ars.2010.3835. Epub 2011 May 25.


Aims: Although oxidative stress participates in the etiopathogenesis of rheumatoid arthritis, its importance in this inflammatory disease has not been fully elucidated. In this study, we analyzed the relevance of the transcription factor Nrf2, master regulator of redox homeostasis, in the effector phase of an animal model of rheumatoid arthritis, using the transfer of serum from K/BxN transgenic mice to Nrf2(-/-) mice.

Results: Nrf2 deficiency accelerated the incidence of arthritis, and animals showed a widespread disease affecting both front and hind paws. Therefore, the inflammatory response was enhanced, with increased migration of leukocytes and joint destruction in front paws. We observed an increased production of tumor necrosis factor-α, interleukin-6, and CXCL-1 in the joint, with small changes in eicosanoid levels. Serum levels of CXCL-1 and receptor activator for nuclear factor κB ligand were enhanced and osteocalcin decreased in arthritic Nrf2(-/-) mice. The expression of cyclooxygenase-2, inducible nitric oxide synthase, and peroxynitrite in the joints was higher in Nrf2 deficiency, whereas heme oxygenase-1 was downregulated.

Innovation: Nrf2 may be a therapeutic target for arthritis.

Conclusion: Our results support a protective role of Nrf2 against joint inflammation and degeneration in arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • Chemokine CXCL1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Heme Oxygenase-1 / metabolism
  • Interleukin-6 / metabolism
  • Joints / metabolism
  • Joints / pathology
  • Mice
  • Mice, Transgenic
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • Tumor Necrosis Factors / metabolism


  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Interleukin-6
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Tumor Necrosis Factors
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Heme Oxygenase-1
  • Cyclooxygenase 2