Linked Life Data

17283078

Source:http://linkedlifedata.com/resource/pubmed/id/17283078

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2007-3-26
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
282
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9492-504
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17283078-Aged, pubmed-meshheading:17283078-Animals, pubmed-meshheading:17283078-Cartilage, Articular, pubmed-meshheading:17283078-Cell Line, Tumor, pubmed-meshheading:17283078-Cells, Cultured, pubmed-meshheading:17283078-DNA-Binding Proteins, pubmed-meshheading:17283078-Down-Regulation, pubmed-meshheading:17283078-Gene Expression Regulation, Neoplastic, pubmed-meshheading:17283078-Homeostasis, pubmed-meshheading:17283078-Humans, pubmed-meshheading:17283078-Inflammation, pubmed-meshheading:17283078-Matrix Metalloproteinases, pubmed-meshheading:17283078-Mice, pubmed-meshheading:17283078-Middle Aged, pubmed-meshheading:17283078-Nuclear Receptor Subfamily 4, Group A, Member 2, pubmed-meshheading:17283078-Transcription, Genetic, pubmed-meshheading:17283078-Transcription Factors
pubmed:year
2007
pubmed:articleTitle
Transcriptional repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in cartilage.
pubmed:affiliation
College of Life Sciences, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland. kimberlee.mix@ucd.ie
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural