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Departments of Biochemistry & Molecular Dentistry,1
Oral & Maxillofacial Rehabilitation,3
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,4
Bio-Dental Research Center, Okayama University Dental School, 2-5-1 Shikata-cho, Okayama City, Okayama 700-8525, Japan2
Received for publication 18 July 2007.
Revision received 14 August 2007.
Accepted for publication 15 December 2007.
Abstract:
Matrix metalloproteinase 3 (MMP3) is well known as a secretoryendopeptidase that degrades extracellular matrices. Recent reportsindicated the presence of MMPs in the nucleus (A. J. Kwon etal., FASEB J. 18:690-692, 2004); however, its function has notbeen well investigated. Here, we report a novel function ofhuman nuclear MMP3 as a trans regulator of connective tissuegrowth factor (CCN2/CTGF). Initially, we cloned MMP3 cDNA asa DNA-binding factor for the CCN2/CTGF gene. An interactionbetween MMP3 and transcription enhancer dominant in chondrocytes(TRENDIC) in the CCN2/CTGF promoter was confirmed by a gel shiftassay and chromatin immunoprecipitation. The CCN2/CTGF promoterwas activated by overexpressed MMP3, whereas a TRENDIC mutantpromoter lost the response. Also, the knocking down of MMP3suppressed CCN2/CTGF expression. By cytochemical and histochemicalanalyses, MMP3 was detected in the nuclei of chondrocytic cellsin culture and also in the nuclei of normal and osteoarthriticchondrocytes in vivo. The nuclear translocation of externallyadded recombinant MMP3 and six putative nuclear localizationsignals in MMP3 also were shown. Furthermore, we determinedthat heterochromatin protein gamma coordinately regulates CCN2/CTGFby interacting with MMP3. The involvement of this novel roleof MMP3 in the development, tissue remodeling, and pathologyof arthritic diseases through CCN2/CTGF regulation thus is suggested.
* Corresponding author. Mailing address: Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama City, Okayama, Japan. Phone: 81-86-235-6645. Fax: 81-86-235-6649. E-mail: takigawa{at}md.okayama-u.ac.jp
Published ahead of print on 2 January 2008.
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