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Novel inhibitors of MMP-1 and MMP-13 gene expression as potential therapies for arthritis.

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Call No.	QP609.C64 M59 2003
Author	Mix, Kimberlee S.
Title	Novel inhibitors of MMP-1 and MMP-13 gene expression as potential therapies for arthritis.
Date	2003
Abstract	Matrix metalloproteinases (MMPs) are a family of endopeptidases that collectively degrade all components of the extracellular matrix (ECM) at neutral pH. During the progression of arthritis, MMPs mediate the degradation of cartilage, which consists largely of type II collagen fibrils and proteoglycans. The collagenases, a subgroup of MMPs, have the singular ability to cleave intact collagens, thus providing the rate-limiting step in cartilage destruction. In arthritic lesions, collagenase-1 (MMP-1) and collagenase-3 (MMP-13) mediate the irreversible destruction of cartilage, suggesting that these enzymes are therapeutic targets. We identified novel inhibitors of MMP-1 and MMP-13 gene expression and characterized the mechanisms contributing to the inhibition of these genes. The synthetic triterpenoid CDDO antagonizes transcriptional induction of MMP-1 and MMP-13 by inflammatory cytokines in human chondrosarcoma cells. CDDO activates the nuclear hormone receptor peroxisome-proliferator activated receptor-gamma (PPAR-gamma), however, we determined that PPAR-gamma is not required for the suppression of MMP-1 or MMP-13 by CDDO. Furthermore, we extended these studies with another PPAR-gamma ligand, the prostaglandin 15dPGJ2, and found that here, too, repression of MMP-1 and MMP-13 gene expression occurs independently of PPAR-gamma. Next, we addressed the impact of CDDO on TGF-beta as a potential pathway contributing to the repression of MMPs and found that the intracellular mediators of TGF-beta signaling, Smad proteins, are involved in the repression of MMP-1 by CDDO. Specifically, Smad3 is required for inhibition, while the inhibitory Smad, Smad7, abrogates repression by CDDO. Finally, we tested the effect of the orphan nuclear receptor NURR1 on MMP-1 transcription, and found that this receptor antagonizes basal and IL-1beta induced MMP-1 promoter activity. Thus, we have elucidated novel inhibitors of MMP-1 and MMP-13 gene expression that may ultimately lead to the development of therapies for arthritis.
Description	x, 255 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Constance E. Brinckerhoff.
Subject	Collagenases -- Genetic aspects. Collagenases -- Pathophysiology. Metalloproteinases -- Genetic aspects. Metalloproteinases -- Pathophysiology. Transcription factors. Extracellular matrix proteins. Cartilage -- Diseases. Arthritis -- Genetic aspects.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.9

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Novel inhibitors of MMP-1 and MMP-13 gene expression as potential therapies for arthritis A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the degree of Doctor of Philosophy In Biochemistry By Kimberlee S. Mix DARTMOUTH COLLEGE Hanover, New Hampshire September 26, 2003 Examining Committee: __________________________ Steven N. Fiering Ph.D. (Chair) __________________________ Constance E. Brinckerhoff Ph.D. __________________________ Michael B. Sporn M.D. __________________________ Anne M. Delany Ph.D. __________________________ Carol Folt Ph.D. Dean of Graduate Studies

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