Connective tissue growth factor causes persistent proα2(l) collagen gene expression induced by transforming growth factor-β in a mouse fibrosis model

被引:89
作者
Chujo, S
Shirasaki, F
Kawara, S
Inagaki, Y
Kinbara, T
Inaoki, M
Takigawa, M
Takehara, K
机构
[1] Kanazawa Univ, Grad Sch Med Sci, Dept Dermatol, Kanazawa, Ishikawa 9208641, Japan
[2] Natl Kanazawa Hosp, Dept Dermatol, Kanazawa, Ishikawa, Japan
[3] Tokai Univ, Sch Med, Dept Community Hlth, Isehara, Kanagawa, Japan
[4] Kawasaki Med Sch, Dept Dermatol, Okayama, Japan
[5] Okayama Univ, Grad Sch Med & Dent, Okayama, Japan
关键词
D O I
10.1002/jcp.20251
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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. (c) 2004 Wiley-Liss, Inc.
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页码:447 / 456
页数:10
相关论文
共 48 条
[1]   Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β [J].
Abreu, JG ;
Ketpura, NI ;
Reversade, B ;
De Robertis, EM .
NATURE CELL BIOLOGY, 2002, 4 (08) :599-604
[2]  
BONNEROT C, 1993, METHOD ENZYMOL, V225, P451
[3]   A potent far-upstream enhancer in the mouse pro alpha 2(I) collagen gene regulates expression of reporter genes in transgenic mice [J].
BouGharios, G ;
Garrett, LA ;
Rossert, J ;
Niederreither, K ;
Eberspaecher, H ;
Smith, C ;
Black, C ;
deCrombrugghe, B .
JOURNAL OF CELL BIOLOGY, 1996, 134 (05) :1333-1344
[4]   CONNECTIVE-TISSUE GROWTH-FACTOR - A CYSTEINE-RICH MITOGEN SECRETED BY HUMAN VASCULAR ENDOTHELIAL-CELLS IS RELATED TO THE SRC-INDUCED IMMEDIATE EARLY GENE-PRODUCT CEF-10 [J].
BRADHAM, DM ;
IGARASHI, A ;
POTTER, RL ;
GROTENDORST, GR .
JOURNAL OF CELL BIOLOGY, 1991, 114 (06) :1285-1294
[5]  
FALANGA V, 1992, Journal of Dermatological Science, V3, P131, DOI 10.1016/0923-1811(92)90026-8
[6]   Costimulation of fibroblast collagen and transforming growth factor beta(1) gene expression by monocyte chemoattractant protein-1 via specific receptors [J].
GharaeeKermani, M ;
Denholm, EM ;
Phan, SH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (30) :17779-17784
[7]   Selective stimulation of collagen synthesis in the presence of costimulatory insulin signaling by connective tissue growth factor in scleroderma fibroblasts [J].
Gore-Hyer, E ;
Pannu, J ;
Smith, EA ;
Grotendorst, G ;
Trojanowska, M .
ARTHRITIS AND RHEUMATISM, 2003, 48 (03) :798-806
[8]  
GRUBER BL, 1994, J IMMUNOL, V152, P5860
[9]  
Hasegawa M, 1999, CLIN EXP IMMUNOL, V117, P159
[10]  
Hasegawa M, 1997, J RHEUMATOL, V24, P328