REGULATION OF COLLAGENASE GENE EXPRESSION

Summary

Principal Investigator: Constance Brinckerhoff
Affiliation: Dartmouth Medical School
Country: USA
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

Top Publications

  1. pmc Differential mechanisms of tumor progression in clones from a single heterogeneous human melanoma
    Walburga Croteau
    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
  2. pmc Analysis of matrix metalloproteinase-1 gene polymorphisms and expression in benign and malignant breast tumors
    Jing Zhou
    Clinical Breast Care Project, Windber Research Institute, Windber, Pennsylvania, PA 15963, USA
    Cancer Invest 29:599-607. 2011
  3. pmc Matrix metalloproteinase and G protein coupled receptors: co-conspirators in the pathogenesis of autoimmune disease and cancer
    Sarah M Eck
    Department of Biochemistry, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
    J Autoimmun 33:214-21. 2009
  4. pmc A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis
    J S Blackburn
    Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
    Oncogene 28:4237-48. 2009
  5. pmc Site controlled transgenic mice validating increased expression from human matrix metalloproteinase (MMP-1) promoter due to a naturally occurring SNP
    Charles I Coon
    Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, NH 03756 Lebanon
    Matrix Biol 28:425-31. 2009
  6. pmc CXCR4 and matrix metalloproteinase-1 are elevated in breast carcinoma-associated fibroblasts and in normal mammary fibroblasts exposed to factors secreted by breast cancer cells
    Sarah M Eck
    Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03756, USA
    Mol Cancer Res 7:1033-44. 2009
  7. pmc PTEN suppression of YY1 induces HIF-2 activity in von-Hippel-Lindau-null renal-cell carcinoma
    Brenda L Petrella
    Department of Medicine, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA
    Cancer Biol Ther 8:1389-401. 2009
  8. pmc Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS
    Jinju Li
    Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA
    Environ Health Perspect 117:400-9. 2009
  9. pmc Retinoid X receptor and peroxisome proliferator-activated receptor-gamma agonists cooperate to inhibit matrix metalloproteinase gene expression
    Peter S Burrage
    Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA
    Arthritis Res Ther 10:R139. 2008
  10. pmc Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis
    Jessica S Blackburn
    Department of Biochemistry, Dartmouth Medical School, Lebanon, NH 03756, USA
    Am J Pathol 173:1736-46. 2008

Scientific Experts

  • WOLFGANG B LIEDTKE
  • Pengcheng Zhu
  • C E Brinckerhoff
  • Kimberlee S Mix
  • Peter S Burrage
  • Jessica S Blackburn
  • Sarah M Eck
  • Charles I Coon
  • Colby A Wyatt
  • Walburga Croteau
  • Jing Zhou
  • C I Coon
  • J S Blackburn
  • Jinju Li
  • S M Eck
  • Brenda L Petrella
  • Matthew P Vincenti
  • Siying Ye
  • Molly H Jenkins
  • David W Mullins
  • Richard Mural
  • Jasmine Saini
  • Craig Shriver
  • Stella Somiari
  • Susan Lubert
  • Kui Yang
  • Jeffrey Hooke
  • Andrew J Ghio
  • B L Petrella
  • Anik L Côté
  • I Liu
  • Justin Gaudet
  • Seung Hyun Cho
  • Sidney A Simon
  • William D Winkelman
  • Adam C Schmucker
  • P J Hoopes
  • Steven Fiering
  • C Harker Rhodes
  • James C Geoghegan

Detail Information

Publications19

  1. pmc Differential mechanisms of tumor progression in clones from a single heterogeneous human melanoma
    Walburga Croteau
    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...
  2. pmc Analysis of matrix metalloproteinase-1 gene polymorphisms and expression in benign and malignant breast tumors
    Jing Zhou
    Clinical Breast Care Project, Windber Research Institute, Windber, Pennsylvania, PA 15963, USA
    Cancer Invest 29:599-607. 2011
    ..MMP-1 2G insertion polymorphism in the invasive group also correlated significantly with the expression of MMP-1 and breast cancer prognostic markers HER2 and P53...
  3. pmc Matrix metalloproteinase and G protein coupled receptors: co-conspirators in the pathogenesis of autoimmune disease and cancer
    Sarah M Eck
    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...
  4. pmc A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis
    J S Blackburn
    Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
    Oncogene 28:4237-48. 2009
    ....
  5. pmc Site controlled transgenic mice validating increased expression from human matrix metalloproteinase (MMP-1) promoter due to a naturally occurring SNP
    Charles I Coon
    Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, NH 03756 Lebanon
    Matrix Biol 28:425-31. 2009
    ..We conclude that these mice represent a model for integration of a single copy of the human MMP-1 promoter into the murine genome, and could be used to study MMP-1 gene expression in a murine system...
  6. pmc CXCR4 and matrix metalloproteinase-1 are elevated in breast carcinoma-associated fibroblasts and in normal mammary fibroblasts exposed to factors secreted by breast cancer cells
    Sarah M Eck
    Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03756, USA
    Mol Cancer Res 7:1033-44. 2009
    ....
  7. pmc PTEN suppression of YY1 induces HIF-2 activity in von-Hippel-Lindau-null renal-cell carcinoma
    Brenda L Petrella
    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...
  8. pmc Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS
    Jinju Li
    Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA
    Environ Health Perspect 117:400-9. 2009
    ....
  9. pmc Retinoid X receptor and peroxisome proliferator-activated receptor-gamma agonists cooperate to inhibit matrix metalloproteinase gene expression
    Peter S Burrage
    Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA
    Arthritis Res Ther 10:R139. 2008
    ..The goals of this study were to evaluate the inhibition of IL-1-beta-induced expression of MMP-1 and MMP-13 by combinatorial treatment with RXR and PPARgamma ligands and to investigate the molecular mechanisms of this inhibition...
  10. pmc Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis
    Jessica S Blackburn
    Department of Biochemistry, Dartmouth Medical School, Lebanon, NH 03756, USA
    Am J Pathol 173:1736-46. 2008
    ....
  11. pmc Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model
    S M Eck
    Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
    Breast Cancer Res Treat 116:79-90. 2009
    ..We conclude that breast cancer-derived MMP-1 mediates invasion through soft tissues and bone via mechanisms involving matrix degradation, angiogenesis, and osteoclast activation...
  12. ncbi RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis
    Jessica S Blackburn
    Department of Biochemistry, Norris Cotton Cancer Center, Lebanon, New Hampshire, USA
    Cancer Res 67:10849-58. 2007
    ....
  13. ncbi Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: can MMPs be good for you?
    Matthew P Vincenti
    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
    ....
  14. ncbi Regulation of matrix metalloproteinase gene expression by a retinoid X receptor-specific ligand
    Peter S Burrage
    Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA
    Arthritis Rheum 56:892-904. 2007
    ....
  15. ncbi Molecular targets in osteoarthritis: metalloproteinases and their inhibitors
    P S Burrage
    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
    ....
  16. ncbi Transcriptional repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in cartilage
    Kimberlee S Mix
    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...
  17. ncbi Short hairpin RNA-mediated inhibition of matrix metalloproteinase-1 in MDA-231 cells: effects on matrix destruction and tumor growth
    Colby 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...
  18. ncbi ADAM22 plays an important role in cell adhesion and spreading with the assistance of 14-3-3
    Pengcheng Zhu
    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...