Novel transcriptional regulation of CCN2/CTGF by nuclear translocation of MMP3

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Citations (Scopus)

Abstract

CCN2/CTGF, previously known as Connective Tissue Growth Factor, is a crucial regulator of extra-cellular matrix (ECM), which promotes ECM synthesis and stabilization. As their family name clearly implies, matrix metalloproteases (MMPs) are also localized in the ECM, where they function as proteases, modulating cell signaling by cleaving proteins such as matrix proteins, growth factors and growth factor receptors. Strong expression of CCN2/CTGF in chondrocytic cells occurs through transcription enhancer dominant in chondrocytes (TRENDIC). Matrix metalloprotease-3 (MMP3) is a novel TRENDIC-binding transcription factor for CCN2/CTGF expression. First, MMP3 cDNA was cloned as a TRENDIC-binding factor by Southwestern screening. The interaction between MMP3 and TRENDIC was confirmed by a gel shift assay and chromatin immunoprecipitation. The CCN2/CTGF promoter was activated by transfected MMP3, whereas a TRENDIC mutant for the promoter lost the response. In addition, the knockdown of MMP3 suppressed CCN2/CTGF expression. Cytochemical and histochemical analyses demonstrated that 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 was observed in 30 min after the addition, and six putative nuclear localization signals were found in MMP3. These results indicated a novel trans-activation mechanism of CCN2/CTGF by the nuclear translocation of MMP3 through binding with TRENDIC in chondrocytes. Although MMPs historically had been recognized as a protease for extra-cellular proteins, this study indicated that it also stimulates ECM synthesis through CCN2/CTGF trans-activation. This novel regulatory role of the ECM may contribute to understanding the mechanism of not only the development, but also the pathogenesis of arthritis fibrosis and periodontitis.

Original languageEnglish
Title of host publicationCCN Proteins in Health and Disease
Subtitle of host publicationAn Overview of the Fifth International Workshop on the CCN Family of Genes
PublisherSpringer Netherlands
Pages255-264
Number of pages10
ISBN (Print)9789048137787
DOIs
Publication statusPublished - 2010

Keywords

  • CCN2/CTGF
  • Chondrocytes
  • Nuclear MMP3
  • Transcription

ASJC Scopus subject areas

  • Medicine(all)

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    Eguchi, T., Kubota, S., Kawata, K., Mukudai, Y., Uehara, J., Ohgawara, T., Ibaragi, S., Sasaki, A., Kuboki, T., & Takigawa, M. (2010). Novel transcriptional regulation of CCN2/CTGF by nuclear translocation of MMP3. In CCN Proteins in Health and Disease: An Overview of the Fifth International Workshop on the CCN Family of Genes (pp. 255-264). Springer Netherlands. https://doi.org/10.1007/978-90-481-3779-4_19