start-ver=1.4
cd-journal=joma
no-vol=203
cd-vols=
no-issue=2
article-no=
start-page=447
end-page=456
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2004
dt-pub=200412
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Connective Tissue Growth Factor Causes Persistent Proƒ¿2(I) Collagen Gene Expression Induced by Transforming Growth Factor-ƒÀ in a Mouse Fibrosis Model
en-subtitle=
kn-subtitle=
en-abstract=
kn-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.
en-copyright=
kn-copyright=

en-aut-name=ChujoSonoko
en-aut-sei=Chujo
en-aut-mei=Sonoko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=ShirasakiFumiaki
en-aut-sei=Shirasaki
en-aut-mei=Fumiaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KawaraShigeru
en-aut-sei=Kawara
en-aut-mei=Shigeru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=InagakiYutaka
en-aut-sei=Inagaki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KinbaraTakuro
en-aut-sei=Kinbara
en-aut-mei=Takuro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=InaokiMakoto
en-aut-sei=Inaoki
en-aut-mei=Makoto
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=TakeharaKazuhiko
en-aut-sei=Takehara
en-aut-mei=Kazuhiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

affil-num=1
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science

affil-num=2
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science

affil-num=3
en-affil=
kn-affil=Department of Dermatology, National Kanazawa Hospital

affil-num=4
en-affil=
kn-affil=Department of Community Health, Tokai University School of Medicine

affil-num=5
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science

affil-num=6
en-affil=
kn-affil=Department of Dermatology, Kawasaki Medical School

affil-num=7
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry

affil-num=8
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science
en-keyword=systemic sclerosis
kn-keyword=systemic sclerosis
en-keyword=fibrosis
kn-keyword=fibrosis
en-keyword=transforming growth factor-?
kn-keyword=transforming growth factor-?
en-keyword=connective tissue growth factor
kn-keyword=connective tissue growth factor
END