Background/Purpose: Nuclear receptor 4A2 (NR4A2 / nuclear receptor related 1 / Nurr1) is a constitutively active transcription factor with diverse roles in normal physiology and disease processes. NR4A2 and related receptor NR4A3 are immediate-early genes potently induced by inflammatory cytokines, growth factors, and prostaglandins in inflamed joints, suggesting that these factors may mediate chronic inflammation. NR4A2 regulates transcription of MMPs and pro-inflammatory cytokines in synoviocytes and chondrocytes, and thus may serve as a novel therapeutic target for modulating inflammatory pathways in arthritis. However, the impact of NR4A expression on the onset and progression of arthritis has not been examined. In the current study, we documented receptor expression in three different murine models of rheumatoid arthritis and correlated NR4A levels with joint inflammation and resolution. 

Methods: Antigen-induced arthritis (AIA), collagen-induced arthritis (CIA), K/BxN serum transfer arthritis (STA) were studied. NR4A2 protein was detected by immunohistochemistry in knee and ankle joints from the AIA and STA models, respectively.  Joint images were processed with CellSens software, and NR4A2 positivity was determined for multiple regions of the synovium and cartilage.   NR4A2 and NR4A3 mRNA levels were also quantified by RT-qPCR in inflamed paws from mice with CIA.  Clinical scores were recorded over the course of disease, and were correlated with protein and mRNA expression levels of the NR4A receptors. 

Results: In the AIA model, NR4A2 protein levels peaked during the inflammatory phase (day 8) and declined to baseline during resolution (day 12), mirroring changes in knee swelling and histological signs of inflammation.  Approximately 45% of synoviocytes and 70% of chondrocytes expressed NR4A2 protein at day 8, and receptor expression was identified in both the cytoplasm and nuclei of these cells. However, in the CIA model, NR4A2 mRNA expression remained low throughout the induction and inflammatory phases, but it was induced 2.5-fold during the resolution phase (day 10 post-onset, p<0.05,).   In contrast, NR4A3 levels peaked during the inflammatory phase of CIA (day 5 post-onset, 2.5-fold, p<0.05) and correlated strongly with clinical scores (Pearson’s r = 0.98). Interestingly, NR4A2 protein was not detected at any stage in the STA model, despite robust inflammation and evidence of joint degradation.   

Conclusion: This study provides evidence for the differential regulation of NR4A receptors in response to distinct pathogenic mechanisms in models of RA. NR4A2 expression coincides with inflammation in AIA and resolution in CIA, a dichotomy that may be due to differences in the effector cytokines driving these models.   Furthermore, the temporal expression patterns of NR4A3 and NR4A2 suggest that these receptors may have distinct transcriptional roles during disease progression.

---

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/nuclear-receptor-4a2-is-differentially-expressed-in-animal-models-of-ra-during-inflammation-and-resolution/