Smad3 mediates the TGF-beta-induced contraction of type I collagen gels by mouse embryo fibroblasts.
TGF-beta signals through TGF-beta receptors and Smad proteins. TGF-beta also augments fibroblast-mediated collagen gel contraction, an in vitro model of connective tissue remodeling. To investigate the importance of Smad2 or Smad3 in this augmentation process, embryo-derived fibroblasts from mice lacking expression of Smad2 or Smad3 genes were cast into native type I collagen gels. Fibroblast-populated gels were then released into 0.2% FCS-DMEM alone or with recombinant human TGF-beta1, beta2, beta3, or recombinant rat PDGF-BB. Gel contraction was determined using an image analyzer. All three isoforms of TGF-beta significantly augmented contraction of collagen gels mediated by fibroblasts with genotypes of Smad2 knockout (S2KO), Smad2 wildtype (S2WT), and Smad3 wildtype (S3WT), but not Smad3 knockout (S3KO) mice. PDGF-BB augmented collagen gel contraction by all fibroblast types. These results suggest that expression of Smad3 but not Smad2 may be critical in TGF-beta augmentation of fibroblast-mediated collagen gel contraction. Thus, the Smad3 gene could be a target for blocking contraction of fibrotic tissue induced by TGF-beta.
Liu
Xiangde
X
Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5125, USA.
Wen
Fu-Qiang
FQ
Kobayashi
Tetsu
T
Abe
Shinji
S
Fang
Qiuhong
Q
Piek
Ester
E
Bottinger
Erwin P
EP
Roberts
Anita B
AB
Rennard
Stephen I
SI
D000818:Animals; D024042:Collagen Type I / Q000502:physiology*; D004247:DNA / Q000032:analysis; D004268:DNA-Binding Proteins / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006909:Hydroxyproline / Q000032:analysis; D051379:Mice; D051900:Smad3 Protein; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D024042:Collagen Type I; D004268:DNA-Binding Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D004247:DNA; D006909:Hydroxyproline