Deficiency of Nrf2 Accelerates the Effector Phase of Arthritis and Aggravates Joint Disease

Abstract

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-a, 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 jB 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. Antioxid. Redox Signal. 15, 889-901.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Deletion of the NRF2 gene increases vulnerability to joint alterations in experimental RA models. For instance, in mice expressing the T cell receptor KRN and the major histocompatibility complex class II molecule A(g7) (the K/BÂN arthritis model), and in antibody-induced arthritis, NRF2 deficiency accelerates the incidence and aggravates the disease course (Maicas et al, 2011;Wu et al, 2016b). NRF2 deficiency dramatically upregulates migration of inflammatory cells, expression of cyclooxygenase-2 and inducible nitric oxide synthase, production of ROS and RNS, and release of proinflammatory cytokines and chemokines.…”

“…NRF2 deficiency dramatically upregulates migration of inflammatory cells, expression of cyclooxygenase-2 and inducible nitric oxide synthase, production of ROS and RNS, and release of proinflammatory cytokines and chemokines. Moreover, NRF2 may be a protective factor for bone metabolism in arthritis (Maicas et al, 2011), and NRF2/HO-1 activation exerts anti-inflammatory and antioxidant effects in animal models of RA and in human synovial fibroblasts (Wu et al, 2016b). It is interesting that antirheumatic gold(I)-containing compounds that stimulate the antioxidant response through activation of NRF2 and upregulation of HO-1 and GCLC proved clinical efficacy in RA .…”

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

“…CDDO blocks the induction of matrix metalloproteinase (MMP)-1 and MMP-13 in chondrosarcoma cells and in primary chondrocytes stimulated with IL-1␤ and TNF-␣, and it inhibits cell invasion through collagen (Mix et al, 2001;Elliott et al, 2003;Mix et al, 2004). These MMPs induce the degradation of cartilage, so inhibiting their production may prevent osteoarthritis or rheumatoid arthritis, and Nrf2 deficiency exacerbates arthritis in mice (Maicas et al, 2011;Wruck et al, 2011). It is noteworthy that CDDO also blocks viral replication in macrophages infected with HIV but not through modulation of cytokines (Vázquez et al, 2005).…”

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes–associated osteoarthritis

“…Likewise, evidence for altered Nrf-2 signaling in aging and metabolic disorders has been reported (19,20). As shown in recent studies, Nrf-2 is a pivotal target for the prevention and attenuation of diabetes mellitus (17,21) and for controlling bone and cartilage destruction induced by oxidative stress (22,23). Under physiological conditions, Nrf-2 is generally located in the cytoplasm and binds to its inhibitor, Kelch-like ECHassociated protein 1 (Keap1), leading to its degradation.…”