Genomes and Genes
REGULATION OF COLLAGENASE GENE EXPRESSION
Principal Investigator: Constance Brinckerhoff
Affiliation: Dartmouth Medical School
Abstract: DESCRIPTION (provided by applicant): In Rheumatoid Arthritis and Osteoarthritis, cartilage, tendon and bone are irreversibly destroyed, largely due to Matrix Metalloproteinases, MMP-1 and MMP-13. Expression of these enzymes in connective tissue cells is induced by the cytokine Interleukin-1( (IL-1(). Since joint destruction is irreversible, therapeutic strategies targeted to block this destruction are attractive. We have found that the RXR-specific ligand, LG268, and the PPAR( ligand, rosiglitazone, selectively inhibit IL-1(-induced production of these MMPs in SW-1353 chondrosarcoma cells, a proven model of chondrocyte biology, and prevent breakdown of collagen by these cells in vitro. When added together, inhibition of gene expression and collagen breakdown is greater than with either compound alone. Suppression of both genes involves changes in histone acetylation and SUMOylation of nuclear receptors. Unexpectedly, the PPAR antagonist, GW-9662, which prevents interaction of the receptor with classical DNA response elements, reduces MMP-13 expression, and further reduces MMP-1 and MMP-13 expression when combined with LG268. Thus, we hypothesize that these compounds act through novel and complex mechanisms, which include genetic and epigenetic components. Mouse models are used to study arthritis pathogenesis, and mouse and human MMP-13 share >80% sequence identity and similar expression patterns. However, mice have only a distant homologue of MMP-1, and the human MMP-1 promoter is unique. It contains a single nucleotide polymorphism (SNP), an ETS site, which is present in 75% of individuals and which augments transcription of this gene. We further hypothesize that the SNP is associated with increased cartilage breakdown in arthritis. We will, therefore, use model systems of primary cultures of human chondrocytes and murine collagen-induced arthritis to test the role of the SNP in matrix destruction and the therapeutic efficacy of LG268 and rosiglitazone in both models. To test our hypotheses, we will: (1 ).Continue to investigate the molecular mechanisms (genetic and epigenetic) by which RXR and PPAR( ligands selectively repress MMP-1 and MMP-13 gene expression;(2). Use the unique PPAR( ligand, GW-9662, to study the differential regulation of MMP-1 vs. MMP-13;and (3). Genotype DNA from human chondrocytes in order to correlate the SNP with levels of MMP-1 production and tissue destruction;and monitor the ability of RXR and PPAR( ligands to block connective tissue destruction in human cells in vitro and ablate disease in experimental arthritis in vivo. These studies will increase our understanding of how MMP-1 and MMP-13 contribute to the pathology of arthritis, and provide the rationale for future studies to test the efficacy of RXR and PPAR( ligands in patients.
Funding Period: 1980-03-01 - 2012-07-31
more information: NIH RePORT
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Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA
J Cell Physiol 228:773-80. 2013..Our data suggest that there are multiple mechanisms for melanoma progression within a tumor, which may require different therapeutic strategies...
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Clinical Breast Care Project, Windber Research Institute, Windber, Pennsylvania, PA 15963, USA
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Department of Biochemistry, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
J Autoimmun 33:214-21. 2009..Even though these agents are more specific in their targets than past therapies, these targets are often shared between RA and cancer, underscoring fundamental similarities between autoimmune disorders and some cancers...
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Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
Oncogene 28:4237-48. 2009....
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Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, NH 03756 Lebanon
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Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03756, USA
Mol Cancer Res 7:1033-44. 2009....
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Department of Medicine, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
Cancer Biol Ther 8:1389-401. 2009..We conclude that wild-type PTEN relieves the repressive nature of YY1 at certain HIF-2alpha target promoters and that this mechanism may promote early renal tumorigenesis resulting from VHL inactivation by increasing HIF-2alpha activity...
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Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA
Environ Health Perspect 117:400-9. 2009....
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Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA
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Department of Biochemistry, Dartmouth Medical School, Lebanon, NH 03756, USA
Am J Pathol 173:1736-46. 2008....
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Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
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- RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesisJessica S Blackburn
Department of Biochemistry, Norris Cotton Cancer Center, Lebanon, New Hampshire, USA
Cancer Res 67:10849-58. 2007....
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Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA
J Cell Physiol 213:355-64. 2007....
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Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA
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Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Rubin Building, Room 602, 1 Medical Center Drive, Lebanon, NH 03756, USA
Curr Drug Targets 8:293-303. 2007....
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College of Life Sciences, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland
J Biol Chem 282:9492-504. 2007..We propose a protective function for NURR1 in cartilage homeostasis by selectively repressing MMP gene expression during inflammation...
- Short hairpin RNA-mediated inhibition of matrix metalloproteinase-1 in MDA-231 cells: effects on matrix destruction and tumor growthColby A Wyatt
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA
Cancer Res 65:11101-8. 2005..027). We conclude that MMP-1 expression is essential for the ability of MDA-231 cells to invade and destroy a collagen matrix and in vivo experiments suggest an important role for MMP-1 in breast tumor growth...
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The State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, China
Biochem Biophys Res Commun 331:938-46. 2005..These results strongly demonstrated a functional role for ADAM22/14-3-3 in cell adhesion and spreading...