Reduced Expression of Connective Tissue Growth Factor (CTGF/CCN2) Mediates Collagen Loss in Chronologically Aged Human Skin

被引:170
作者
Quan, TaiHao [1 ]
Shao, Yuan [1 ]
He, Tianyuan [1 ]
Voorhees, John J. [1 ]
Fisher, Gary J. [1 ]
机构
[1] Univ Michigan, Dept Dermatol, Sch Med, Ann Arbor, MI 48109 USA
关键词
FACTOR-BETA; TGF-BETA; MATRIX METALLOPROTEINASE-1; EXTRACELLULAR-MATRIX; RECEPTOR KINASE; GENE-PRODUCT; IN-VIVO; CCN2; INDUCTION; ADHESION;
D O I
10.1038/jid.2009.224
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Reduced production of type I procollagen is a prominent feature of chronologically aged human skin. Connective tissue growth factor (CTGF/CCN2), a downstream target of the transforming growth factor-beta (TGF-beta)/Smad pathway, is highly expressed in numerous fibrotic disorders, in which it is believed to stimulate excessive collagen production. CTGF is constitutively expressed in normal human dermis in vivo, suggesting that CTGF is a physiological regulator of collagen expression. We report here that the TGF-beta/Smad/CTGF axis is significantly reduced in dermal fibroblasts, the major collagen-producing cells, in aged (>= 80 years) human skin in vivo. In primary human skin fibroblasts, neutralization of endogenous TGF-beta or knockdown of CTGF substantially reduced the expression of type I procollagen mRNA, protein, and promoter activity. In contrast, overexpression of CTGF stimulated type I procollagen expression, and increased promoter activity. Inhibition of TGF-beta receptor kinase, knockdown of Smad4, or overexpression of inhibitory Smad7 abolished CTGF stimulation of type I procollagen expression. However, CTGF did not stimulate Smad3 phosphorylation or Smad3-dependent transcriptional activity. These data indicate that in human skin fibroblasts, type I procollagen expression is dependent on endogenous production of both TGF-beta and CTGF, which act through interdependent yet distinct mechanisms. Downregulation of the TGF-beta/Smad/CTGF axis likely mediates reduced type I procollagen expression in aged human skin in vivo.
引用
收藏
页码:415 / 424
页数:10
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