Background/Purpose: The orphan nuclear receptor 4A2 (NR4A2 / NURR1) is emerging as a critical transcription factor in chronic inflammatory joint diseases. We have demonstrated elevated expression of NR4A2 in joint tissues from patients with arthritis, and this receptor promotes synovial hyperplasia and cartilage degradation in vitro.  NR4A2 transactivates the MMP-13, IL-8, and prolactin promoters in synovial fibroblasts and may therefore contribute to the onset and progression of arthritis.  TNF-alpha rapidly and potently induces NR4A2 expression and nuclear localization, suggesting that NR4A2 controls transcriptional responses to inflammation in vivo.  The current study tests the hypothesis that NR4A2 is an early transcriptional mediator of synovial inflammation in the human TNF-alpha transgenic mouse model of rheumatoid arthritis.

Methods: The hTNF-alpha transgenic model exhibits deregulated expression of the human proinflammatory cytokine due to incorporation of the beta-globin 3’ UTR which stabilizes the transcript (Taconic Biosciences, Model 1006).  Mice develop severe polyarthritis by 10 weeks of age with 100% penetrance.  To address early changes in gene expression, RNA was extracted from 8-week old male hTNF-alpha and wild-type mice and NR4A1-3 mRNA was detected by RT-qPCR. Gene expression patterns were compared between hTNF-alpha and wild-type joints using RT-qPCR panels specific for 88 genes involved in RA pathogenesis and housekeeping controls. 

Results: Joints from 8-week old hTNF-alpha mice lacked clinical signs of arthritis, yet several genes involved in pathogenesis were upregulated:  CCL5 (15-fold), IL-1-beta (13-fold), TNFRSF1b(10-fold), ICAM1 (7-fold), CCR5 (5-fold), TNF (5-fold), IL-6 (4-fold), NF-kappa-B (3-fold), and CREB (2-fold).  All three NR4A receptors were expressed at detectable levels by RT-qPCR, however only NR4A2 was selectively increased by 50% in the forepaws and hindpaws of hTNF-alpha mice relative to wild-type controls (p<0.05).  

Conclusion: Upregulation of NR4A2 mRNA precedes clinical signs of arthritis in the hTNF-alpha model, suggesting that NR4A2 is an early transcriptional mediator of synovial inflammation.  In line with this, several genes involved in inflammation and cell signaling are expressed at elevated levels, demonstrating that molecular pathogenesis is underway.  Future studies will examine the expression and distribution of NR4A2 throughout the course of disease and examine the therapeutic potential of targeting NR4A2 in the hTNF-alpha model of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nuclear-receptor-4a2-is-selectively-upregulated-in-the-human-tnf-alpha-transgenic-model-of-rheumatoid-arthritis/