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Abstract Number: 898

Nuclear Receptor Related 1 Induces Synovial Hyperplasia Via Transcriptional Regulation of Novel Target Genes

Kimberlee S. Mix, Biological Sciences, Loyola University New Orleans, New Orleans, LA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Nuclear hormone receptor, synovial cells, synovial fluid and transcription factor

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Session Information

Session Title: Cytokines, Mediators, and Gene Regulation

Session Type: Abstract Submissions (ACR)

Background/Purpose: Nuclear receptor related 1 (NURR1 / NR4A2) is an orphan member of the nuclear receptor super-family that functions as a constitutively active transcription factor. This receptor has critical functions in the central nervous system, where it is required for the proper development of dopaminergic neurons. Furthermore, recent studies suggest that NURR1 promotes inflammatory diseases such as cancer, multiple sclerosis, and diabetes. We have documented over-expression of NURR1 in inflamed synovial tissues and cartilage from patients with rheumatoid arthritis and osteoarthritis. NURR1 is rapidly and potently induced by inflammatory cytokines, suggesting that this receptor may promote disease progression and tissue destruction.  We have recently demonstrated that NURR1 induces a hyperplastic phenotype in fibroblast-like synoviocytes by increasing proliferation, anchorage-independent growth, and invasion.   In the current study, we seek to elucidate the molecular mechanisms of NURR1 and identify downstream transcriptional targets of this receptor that may contribute to synovitis and cartilage degradation. 

Methods: To achieve elevated levels of NURR1 similar to those observed in inflamed synovial tissues, NURR1 cDNA was transduced into normal human synoviocytes.  Transcriptional activity was confirmed by the activation of a consensus NURR1 reporter construct. Quantitative RT-PCR arrays were used to identify genes that were differentially regulated by NURR1. 

Results: Paralleling the effects of TNF-alpha, NURR1 regulates a subset of genes involved in angiogenesis, proliferation, and apoptosis. NURR1 potently induces expression of prolactin (300-fold), a peptide hormone that enhances synoviocyte activation and lymphocyte recruitment.   Angiopoietin-1, a ligand for endothelium-specific tyrosine kinase receptors involved in synovial angiogenesis was induced by NURR1 (6-fold). Expression of the tyrosine kinase receptor TEK was also induced (30-fold), suggesting activation of an autocrine signaling pathway in synoviocytes.  Raf kinase and the downstream mitogenic transcription factor c-Myc were both induced 3-fold by NURR1. Furthermore, the tumor suppressor gene p53 was synergistically repressed by NURR1 and TNF-alpha, suggesting that NURR1 may block DNA repair mechanisms and prevent apoptosis of synoviocytes.

Conclusion: Taken together, we have identified a novel set of NURR1 target genes that converge on multiple pathways regulating synovial hyperplasia.  We hypothesize that antagonizing NURR1 activity with a small molecule inhibitor may provide an innovative strategy to block pannus formation and tissue destruction.


Disclosure:

K. S. Mix,
None;

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