Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation

被引:231
|
作者
Grotendorst, GR [1 ]
Rahmanie, H [1 ]
Duncan, MR [1 ]
机构
[1] Univ Miami, Sch Med, Dept Cell Biol & Anat, RMSB 2030 A, Miami, FL 33136 USA
来源
FASEB JOURNAL | 2004年 / 18卷 / 03期
关键词
myofibroblasts; TGF-beta; CTGF; fibrotic tissue;
D O I
10.1096/fj.03-0699com
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Fibroblast proliferation, differentiation into myofibroblasts, and increased collagen synthesis are key events during both normal wound repair and fibrotic lesion formation. Here we report that these biological responses to TGF-beta by fibroblasts are regulated via a CTGF-dependent pathway in concert with either EGF or IGF-2. Our studies indicate these responses to TGF-beta are mutually exclusive, and cells that are proliferating do not express alpha-SMA or elevated levels of collagen synthesis. Cells expressing alpha-SMA do not exhibit DNA synthesis but do coexpress higher levels of types I and III collagen mRNA. Thus, fibroblast proliferation and differentiation are controlled by combinatorial signaling pathways involving not only components of the TGF-beta/CTGF pathway, but also signaling events induced by EGF and IGF-2-activated receptors. Collectively, our studies indicate TGF-beta functions as a classic embryonic inducer, initiating a cascade that is controlled by other factors in the cellular environment. We propose a model for this process with regard to wound repair and fibrotic lesion formation that is likely applicable to other instances of CTGF action during embryogenesis.
引用
收藏
页码:469 / 479
页数:11
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