このエントリーをはてなブックマークに追加
ID 32995
FullText URL
Author
Chujo, Sonoko
Shirasaki, Fumiaki
Kawara, Shigeru
Inagaki, Yutaka
Kinbara, Takuro
Inaoki, Makoto
Takehara, Kazuhiko
Abstract
Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive production of extracellular matrix (ECM) and understood to develop under the influence of certain growth factors. Connective tissue growth factor (CTGF) is a cysteine-rich mitogenic peptide that is implicated in various fibrotic disorders and induced in fibroblasts after activation with transforming growth factor-beta (TGF-beta). To better understand the mechanisms of persistent fibrosis seen in SSc, we previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, TGF-beta transiently induced subcutaneous fibrosis and serial injections of CTGF after TGF-beta caused persistent fibrosis. To further define the mechanisms of skin fibrosis induced by TGF-beta and CTGF in vivo, we investigated in this study, the effects of growth factors on the promoter activity of the pro alpha 2 (1) collagen (COL1A2) gene in skin fibrosis. For this purpose, we utilized transgenic reporter mice harboring the -17 kb promoter sequence of the mouse COL1A2 linked to either a firefly luciferase gene or a bacterial P-galactosidase gene. Serial injections of CTGF after TGF-beta resulted in a sustained elevation of COL1A2 mRNA expression and promoter activity compared with consecutive injection of TGF-beta alone on day 8. We also demonstrated that the number of fibroblasts with activated COL1A2 transcription was increased by serial injections of CTGF after TGF-beta in comparison with the injection of TGF-beta alone. Furthermore, the serial injections recruited mast cells and macrophages. The number of mast cells reached a maximum on day 4 and remained relatively high up to day 8. In contrast to the kinetics of mast cells, the number of macrophages was increased on day 4 and continued to rise during the subsequent consecutive CTGF injections until day 8. These results suggested that CTGF maintains TGF-beta-induced skin fibrosis by sustaining COL1A2 promoter activation and increasing the number of activated fibroblasts. The infiltrated mast cells and macrophages may also contribute to the maintenance of fibrosis.
Keywords
systemic sclerosis
fibrosis
transforming growth factor-?
connective tissue growth factor
Note
Digital Object Identifer:10.1002/jcp.20251
Published with permission from the copyright holder. This is the institute's copy, as published in the Journal of Cellular Physiology, December 2004, Volume 203, Issue 2, Pages 447-456.
Publisher URL:http://dx.doi.org/10.1002/jcp.20251
Direct access to Thomson Web of Science record
Copyright © 2004 Wiley-Liss, Inc. All rights reserved.
Published Date
2004-12
Publication Title
Journal of Cellular Physiology
Volume
volume203
Issue
issue2
Publisher
Wiley-Liss
Start Page
447
End Page
456
ISSN
0021-9541
NCID
AA00694856
Content Type
Journal Article
language
英語
Copyright Holders
Wiley-Liss, Inc.
File Version
author
Refereed
True
DOI
Web of Sience KeyUT
Submission Path
biology_general/33