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Mol. Cell. Biol. doi:10.1128/MCB.01288-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Novel Transcription Factor-like Function of Human MMP3 Regulating CTGF/CCN2 Gene

Departments of Biochemistry & Molecular Dentistry, Oral & Maxillofacial Rehabilitation, and Oral & Maxillofacial Surgery & Biopathology; Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,, 2-5-1 Shikata-cho, Okayama City, Okayama 700-8525, Japan; Bio-Dental Research Center, Okayama University Dental School, 2-5-1 Shikata-cho, Okayama City, Okayama 700-8525, Japan

^* To whom correspondence should be addressed. Email: takigawa{at}md.okayama-u.ac.jp.

	Abstract

Matrix metalloproteinase-3 (MMP3) is well known as a secretory endopeptidase degrading extracellular matrices. Recent reports indicated the presence of MMPs in the nucleus; however, its function has not been well investigated. Here, we report a novel function of human nuclear MMP3 as a trans-regulator of connective tissue growth factor (CCN2/CTGF). Initially, we cloned MMP3 cDNA as a DNA-binding factor for the CCN2/CTGF gene. Interaction between MMP3 and TRENDIC (transcription enhancer dominant in chondrocytes) in the CCN2/CTGF promoter was confirmed by a gel shift assay and chromatin immunoprecipitation. The CCN2/CTGF promoter was activated by overexpressed MMP3, whereas a TRENDIC-mutant promoter lost the response. Also, knocking-down of MMP3 suppressed CCN2/CTGF expression. By cytochemical and histochemical analysis, MMP3 was detected in the nucleus of chondrocytic cells in culture, and also in the nucleus of normal and osteoarthritic chondrocytes in vivo. Nuclear translocation of externally added recombinant MMP3 and 6 putative nuclear localization signals in MMP3 were also shown. Furthermore, we identified HP1 coordinately regulates the CCN2/CTGF by interacting with MMP3. Involvement of this novel role of MMP3 in developments, tissue remodeling, and pathology of arthritic diseases through CCN2/CTGF regulation is thus suggested.