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J. Biol. Chem., Vol. 282, Issue 13, 9492-9504, March 30, 2007

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Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage^*

Kimberlee S. Mix¹, Mukundan G. Attur, Hayf Al-Mussawir, Steven B. Abramson, Constance E. Brinckerhoff^¶, and Evelyn P. Murphy

From the College of Life Sciences, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland, the Division of Rheumatology, New York University Hospital for Joint Diseases, New York, New York 10003, and the ^¶Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756

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 E₂ (PGE₂) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE₂-mediated processes in cartilage. We demonstrate that PGE₂ represses interleukin-1-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.

Received for publication, August 31, 2006 , and in revised form, February 1, 2007.

^* This work was supported by grants from the Health Research Board (to K. S. M.) and the Science Foundation Ireland (to E. P. M.) and by National Institutes of Heath Grant AR-26599 (to C. E. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed. Tel.: 353-1-716-6213; Fax: 353-1-716-6219; E-mail: kimberlee.mix{at}ucd.ie.

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