Human development, growth and health critically depends on tissue remodeling and the exquisite balance between the synthesis and degradation of connective tissues. At times, inconsistencies in tissue remodeling result in developmental anomalies and devastating connective tissue diseases that can affect the skin, blood vessels, bone and cartilage of the joints. A number of these diseases are known to be genetic and inherited and are the result of structural mutations in the genes that encode collagen, the most abundant proteins of the body. In many acquired type of connective tissue diseases such as osteoarthritis and rheumatoid arthritis, the underlying causes have not been identified. However, increasing evidence suggests a critical role for the connective tissued degrading enzymes or matrix metalloproteinases, growth factors and inflammatory cytokines in the pathogenesis of arthritic joint destruction. We hypothesize that tissue remodeling is largely controlled by the expression of matrix metalloproteinases. Accordingly, in this proposal, we will study the regulation of expression of matrix metalloproteinases at a genetic level, using mutational analysis and transient gene transfection of cultured cells. In particular, we plan to study the activation and inhibition of tissue collagenase and stromelysin genes by cytokines and growth factors including IL-1beta, TNFalpha and FGF, and hormones such as glucocorticoids and retinoic acid. Recently, we and others have shown that several proto-oncogenes are involved in the expression and regulation of matrix metalloproteinase genes. We therefore also propose to systematically study a wide variety of different oncoprotein and transcription factors for their effects on collagenase ad stromelysin gene expression and for their role in the regulation induced by cytokines, growth factors and glucocorticoid and retinoid hormones. As long term goals, research applications of these studies are targeted for the regulation of matrix metalloproteinase genes in vivo, and the treatment and prevention of major connective tissue disorders and diseases such as arthritis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD024442-07
Application #
2199162
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-08-01
Project End
1997-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Wayne State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Yang, M; Kurkinen, M (1998) Cloning and developmental regulation of tissue inhibitor of metalloproteinases-3 (TIMP3) in Xenopus laevis early embryos. Gene 211:95-100
Yang, M; Kurkinen, M (1998) Cloning and characterization of a novel matrix metalloproteinase (MMP), CMMP, from chicken embryo fibroblasts. CMMP, Xenopus XMMP, and human MMP19 have a conserved unique cysteine in the catalytic domain. J Biol Chem 273:17893-900
Yang, M; Murray, M T; Kurkinen, M (1997) A novel matrix metalloproteinase gene (XMMP) encoding vitronectin-like motifs is transiently expressed in Xenopus laevis early embryo development. J Biol Chem 272:13527-33
Benbow, U; Buttice, G; Nagase, H et al. (1996) Characterization of the 46-kDa intermediates of matrix metalloproteinase 3 (stromelysin 1) obtained by site-directed mutation of phenylalanine 83. J Biol Chem 271:10715-22
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Yang, M; Hayashi, K; Hayashi, M et al. (1996) Cloning and developmental expression of a membrane-type matrix metalloproteinase from chicken. J Biol Chem 271:25548-54
Yang, M; Kurkinen, M (1994) Different mechanisms of regulation of the human stromelysin and collagenase genes. Analysis by a reverse-transcription-coupled-PCR assay. Eur J Biochem 222:651-8
Buttice, G; Kurkinen, M (1994) Oncogenes control stromelysin and collagenase gene expression. Contrib Nephrol 107:101-7
Quinones, S; Buttice, G; Kurkinen, M (1994) Promoter elements in the transcriptional activation of the human stromelysin-1 gene by the inflammatory cytokine, interleukin 1. Biochem J 302 ( Pt 2):471-7
Buttice, G; Kurkinen, M (1993) A polyomavirus enhancer A-binding protein-3 site and Ets-2 protein have a major role in the 12-O-tetradecanoylphorbol-13-acetate response of the human stromelysin gene. J Biol Chem 268:7196-204

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