QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mix, K. S. Articles by Brinckerhoff, C. E. Search for Related Content PubMed PubMed Citation Articles by Mix, K. S. Articles by Brinckerhoff, C. E.

Peroxisome Proliferator-Activated Receptor--Independent Repression of Collagenase Gene Expression by 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid and Prostaglandin 15-Deoxy-(12,14) J₂: A Role for Smad Signaling

Departments of Biochemistry (K.S.M., C.E.B.), Medicine (C.I.C., C.E.B.), and Pharmacology and Toxicology (M.B.S., N.S.), Dartmouth Medical School, Hanover, New Hampshire; and Division of Endocrinology (E.D.R.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Matrix metalloproteinases (MMPs) degrade extracellular matrix components, and overexpression of these enzymes contributes to tissue destruction in arthritis. Of particular importance are the collagenases, MMP-1 and MMP-13, which have high activity against the interstitial collagens in cartilage. In this study, we address the mechanisms of two inhibitors of collagenase gene expression, the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-prostaglandin J₂ (15-dPGJ₂). Although both inhibitors are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor- (PPAR-), a connection between PPAR- and collagenase gene expression has yet to be established. Here, we test the hypothesis that CDDO and 15-dPGJ₂ use PPAR- to repress MMP gene expression. Our findings with the PPAR- antagonist 2-[4-[2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl]rsqb]-phenylsulfanyl]-2-methylpropionic acid (GW9662) and mouse embryonic fibroblasts lacking PPAR- demonstrate that CDDO and 15-dPGJ₂ use PPAR--independent mechanisms to inhibit collagenase gene expression. To address a potential PPAR--independent mechanism leading to the repression of MMPs by CDDO, we tested the effect of CDDO on the transforming growth factor- (TGF-) signaling pathway. We found that CDDO requires Smads (transcription factors activated by TGF-) for the repression of MMP-1. Specifically, MMP-1 is inhibited neither by CDDO in the absence of TGF- receptor-activated Smad3 nor when a negative regulator, Smad7, attenuates TGF- signaling. We conclude that CDDO represses MMP gene expression through a novel PPAR--independent mechanism that requires Smad signaling.

Address correspondence to: Constance E. Brinckerhoff, Departments of Biochemistry and Medicine, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756. E-mail: constance.e.brinckerhoff{at}dartmouth.edu

This article has been cited by other articles:

				C. To, S. Kulkarni, T. Pawson, T. Honda, G. W. Gribble, M. B. Sporn, J. L. Wrana, and G. M. Di Guglielmo The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid-Imidazolide Alters Transforming Growth Factor {beta}-dependent Signaling and Cell Migration by Affecting the Cytoskeleton and the Polarity Complex J. Biol. Chem., April 25, 2008; 283(17): 11700 - 11713. [Abstract] [Full Text] [PDF]

				S. Koschmieder, F. D'Alo, H. Radomska, C. Schoneich, J. S. Chang, M. Konopleva, S. Kobayashi, E. Levantini, N. Suh, A. Di Ruscio, et al. CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha Blood, November 15, 2007; 110(10): 3695 - 3705. [Abstract] [Full Text] [PDF]

				K. S. Mix, M. G. Attur, H. Al-Mussawir, S. B. Abramson, C. E. Brinckerhoff, and E. P. Murphy Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage J. Biol. Chem., March 30, 2007; 282(13): 9492 - 9504. [Abstract] [Full Text] [PDF]

				P. Lei, M. Abdelrahim, and S. Safe 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2324 - 2336. [Abstract] [Full Text] [PDF]

				H. A. Burgess, L. E. Daugherty, T. H. Thatcher, H. F. Lakatos, D. M. Ray, M. Redonnet, R. P. Phipps, and P. J. Sime PPAR{gamma} agonists inhibit TGF-{beta} induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1146 - L1153. [Abstract] [Full Text] [PDF]

				M. Francois, P. Richette, L. Tsagris, M. Raymondjean, M.-C. Fulchignoni-Lataud, C. Forest, J.-F. Savouret, and M.-T. Corvol Peroxisome Proliferator-activated Receptor-{gamma} Down-regulates Chondrocyte Matrix Metalloproteinase-1 via a Novel Composite Element J. Biol. Chem., July 2, 2004; 279(27): 28411 - 28418. [Abstract] [Full Text] [PDF]