Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis

Arthritis Rheum. 2000 Oct;43(10):2230-9. doi: 10.1002/1529-0131(200010)43:10<2230::AID-ANR10>3.0.CO;2-8.


Objective: We hypothesized that pathophysiologic events during the development of systemic sclerosis (SSc) may lead to selection and propagation of certain apoptosis-resistant fibroblast subpopulations. The aim of this study was to examine a possible role for apoptosis in fibroblast selection in SSc and the role of transforming growth factor beta1 (TGFbeta1).

Methods: We compared SSc and normal fibroblasts for their susceptibility to anti-Fas-induced apoptosis and analyzed 2 models that might lead to fibroblast resistance to apoptosis in this process: long-term exposure to either anti-Fas or TGFbeta1.

Results: SSc-derived fibroblasts were resistant to anti-Fas-induced apoptosis, showing 5.5 +/- 17.2% (mean +/- SD) apoptosis, compared with 32.1 +/- 14.0% among normal fibroblasts (P < 0.05). Anti-Fas-selected normal fibroblasts showed 9.0 +/- 3.7% apoptosis, compared with 21.6 +/- 5.9% for sham-treated cells, which is consistent with the elimination of apoptosis-susceptible subpopulations. Normal fibroblasts subjected to 6 weeks of TGFbeta1 treatment showed not only resistance to apoptosis, but also proliferation (118.5 +/- 35.4%), after anti-Fas treatment, compared with sham-treated cells (35.1 +/- 11.1% apoptotic cell death). TGFbeta1 treatment also increased the proportion of myofibroblasts (47% versus 28% in controls). Cultured SSc fibroblasts had a greater proportion of myofibroblasts (32-83%) than did normal fibroblasts (4-25%). We also examined the relationship between collagen gene expression and the myofibroblast phenotype in normal and SSc skin sections. Only 2 of 7 normal sections had alpha-smooth muscle actin (a-SMA)-positive cells (mean +/- SD score 0.29 +/- 0.49 on a scale of 0-3), but all SSc sections were positive for alpha-SMA, with a mean score of 1.90 +/- 0.88 for lesional and 1.50 +/- 0.71 for nonlesional sections. Scores for alpha1(I) procollagen messenger RNA (mRNA) in lesional skin (mean +/- SD 3.30 +/- 0.82 on a scale of 1-4) were significantly higher than in normal (1.43 +/- 0.79) or nonlesional (1.40 +/- 0.52) skin, but scores varied, and there was no correlation between collagen mRNA and alpha-SMA levels.

Conclusion: Our results show that resistance to apoptosis is an important part of the SSc phenotype. TGFbeta1 may play a role by inducing apoptosis-resistant fibroblast populations, and also by inducing myofibroblasts and by enhancing extracellular matrix synthesis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / analysis
  • Adult
  • Aged
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Murine-Derived
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Collagen / biosynthesis
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Male
  • Middle Aged
  • Muscle, Smooth / chemistry
  • Phenotype
  • Scleroderma, Systemic / pathology*
  • Scleroderma, Systemic / physiopathology*
  • Skin / metabolism
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1


  • Actins
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • anti-Fas monoclonal antibody
  • Collagen