Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts

Am J Pathol. 2005 May;166(5):1451-63. doi: 10.1016/s0002-9440(10)62362-0.


The extracellular matrix (ECM) glycoprotein thrombospondin-1 (TSP-1) has been reported to activate the latent complex of transforming growth factor-beta (TGF-beta), the major effects of which in mesenchymal cells is stimulation of the synthesis of ECM. Previous reports suggested the involvement of an autocrine TGF-beta loop in the pathogenesis of scleroderma. In this study, we examined whether TSP-1 plays a role in maintaining the autocrine TGF-beta loop in scleroderma. TSP-1 expression was increased in scleroderma patients compared with in healthy controls in vivo and in vitro. TGF-beta blocking antibody or TGF-beta1 antisense oligonucleotide markedly reduced the up-regulated TSP-1 expression in scleroderma fibroblasts but had little effect on normal fibroblasts. The expression of TSP-1 is up-regulated in scleroderma fibroblasts, possibly at the post-transcriptional level just like in normal fibroblasts stimulated with exogenous TGF-beta1. TSP-1 blocking peptide or antisense oligonucleotide had an inhibitory effect on the up-regulated alpha2I collagen and phosopho-Smad3 levels in scleroderma fibroblasts but had little effects on normal fibroblasts. The transient overexpression of TSP-1 up-regulated alpha2I collagen and phospho-Smad3 levels in normal fibroblasts but had no major effect on scleroderma fibroblasts. Furthermore, these effects of transiently overexpressed TSP-1, which possibly occurred via the activation of latent TGF-beta1, were abolished by the TGF-beta1 antisense oligonucleotide. These results indicate that the constitutive overexpression of TSP-1 may play an important role in autocrine TGF-beta signaling and accumulation of ECM in scleroderma fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autocrine Communication*
  • Case-Control Studies
  • Cells, Cultured
  • Collagen / genetics
  • Collagen / metabolism
  • Collagen Type I / metabolism
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Phosphorylation
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / metabolism
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / physiopathology*
  • Signal Transduction*
  • Skin / metabolism
  • Smad3 Protein
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta1
  • Up-Regulation


  • Collagen Type I
  • DNA-Binding Proteins
  • RNA, Messenger
  • SMAD3 protein, human
  • Smad3 Protein
  • TGFB1 protein, human
  • Thrombospondin 1
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Collagen