Transcriptional repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in cartilage.
The NR4A orphan receptors (Nur77, NURR1, and NOR-1) are emerging as key regulators of cytokine and growth factor action in chronic inflammatory diseases. In this study, we address the role of these receptors in cartilage homeostasis during inflammatory joint disease. We document for the first time expression of the NR4A receptors in osteoarthritic cartilage. Relative to Nur77 and NOR-1, NURR1 is expressed at the highest level and correlates with cyclooxygenase-2 levels in cartilage. Consistent with this observation, cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE(2)-mediated processes in cartilage. We demonstrate that PGE(2) represses interleukin-1beta-induced matrix metalloproteinase (MMP)-1 and that transient overexpression of NURR1 is sufficient to antagonize expression of this gene. Furthermore, MMP-1 promoter activity is potently suppressed by NURR1, resulting in a significant reduction in endogenous MMP-1 mRNA and secreted pro-MMP-1 protein. In addition, NURR1 selectively antagonizes cytokine-induced MMP-3 and -9 expression with minimal effects on MMP-2 and -13 and tissue inhibitor of matrix metalloproteinases-1 and -2. To explore the molecular mechanisms of NURR1 transrepression, we reveal that this receptor targets a critical region of the MMP-1 promoter (-1772 to -1546 bp) and that repression does not require consensus binding sites for NURR1. We confirm that NURR1 targets a 40-bp promoter sequence that is also positively regulated by ETS transcription factors. Finally, functional studies indicate that transcriptional antagonism exists between NURR1 and ETS1 on the MMP-1 promoter. We propose a protective function for NURR1 in cartilage homeostasis by selectively repressing MMP gene expression during inflammation.
Mix
Kimberlee S
KS
College of Life Sciences, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: kimberlee.mix@ucd.ie.
Attur
Mukundan G
MG
Division of Rheumatology, New York University Hospital for Joint Diseases, New York, New York 10003.
Al-Mussawir
Hayf
H
Division of Rheumatology, New York University Hospital for Joint Diseases, New York, New York 10003.
Abramson
Steven B
SB
Division of Rheumatology, New York University Hospital for Joint Diseases, New York, New York 10003.
Brinckerhoff
Constance E
CE
Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756.
Murphy
Evelyn P
EP
College of Life Sciences, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.
D000368:Aged; D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D004268:DNA-Binding Proteins; D061965:Matrix Metalloproteinase Inhibitors; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D020782:Matrix Metalloproteinases