Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Mol. Cell. Biol. 28 (7): 2391-2413

Copyright © 2008 by the American Society for Microbiology. All rights reserved.

Novel Transcription Factor-Like Function of Human Matrix Metalloproteinase 3 Regulating the CTGF/CCN2 Gene{triangledown}

Takanori Eguchi,1 Satoshi Kubota,1 Kazumi Kawata,1 Yoshiki Mukudai,2 Junji Uehara,3 Toshihiro Ohgawara,1 Soichiro Ibaragi,4 Akira Sasaki,4 Takuo Kuboki,3, and Masaharu Takigawa1,2*

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 secretory endopeptidase that degrades extracellular matrices. Recent reports indicated the presence of MMPs in the nucleus (A. J. Kwon et al., FASEB J. 18:690-692, 2004); 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. An interaction between MMP3 and transcription enhancer dominant in chondrocytes (TRENDIC) 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, the knocking down of MMP3 suppressed CCN2/CTGF expression. By cytochemical and histochemical analyses, MMP3 was detected in the nuclei of chondrocytic cells in culture and also in the nuclei of normal and osteoarthritic chondrocytes in vivo. The nuclear translocation of externally added recombinant MMP3 and six putative nuclear localization signals in MMP3 also were shown. Furthermore, we determined that heterochromatin protein gamma coordinately regulates CCN2/CTGF by interacting with MMP3. The involvement of this novel role of MMP3 in the development, tissue remodeling, and pathology of 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}

{triangledown} Published ahead of print on 2 January 2008.

Inhibition of Notch signalling ameliorates experimental inflammatory arthritis.
J.-S. Park, S.-H. Kim, K. Kim, C.-H. Jin, K. Y. Choi, J. Jang, Y. Choi, A.-R. Gwon, S.-H. Baik, U. J. Yun, et al. (2013)
Ann Rheum Dis
   Abstract »    Full Text »
MT1-MMP regulates the PI3K{delta}{middle dot}Mi-2/NuRD-dependent control of macrophage immune function.
R. Shimizu-Hirota, W. Xiong, B. T. Baxter, S. L. Kunkel, I. Maillard, X.-W. Chen, F. Sabeh, R. Liu, X.-Y. Li, and S. J. Weiss (2012)
Genes & Dev. 26, 395-413
   Abstract »    Full Text »    PDF »
Role of Matrix Metalloproteinase 3-mediated {alpha}-Synuclein Cleavage in Dopaminergic Cell Death.
D.-H. Choi, Y.-J. Kim, Y.-G. Kim, T. H. Joh, M. F. Beal, and Y.-S. Kim (2011)
J. Biol. Chem. 286, 14168-14177
   Abstract »    Full Text »    PDF »
Stage-specific Control of Connective Tissue Growth Factor (CTGF/CCN2) Expression in Chondrocytes by Sox9 and {beta}-Catenin.
B.-L. Huang, S. M. Brugger, and K. M. Lyons (2010)
J. Biol. Chem. 285, 27702-27712
   Abstract »    Full Text »    PDF »
Involvement of matrix metalloproteinases in the growth plate response to physiological mechanical load.
A. Reich, S. S. Maziel, Z. Ashkenazi, and E. M. Ornan (2010)
J Appl Physiol 108, 172-180
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882