Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis

Arthritis Rheum. 2008 Sep;58(9):2854-65. doi: 10.1002/art.23791.


Objective: Recent studies have implicated caveolin 1 in the regulation of transforming growth factor beta (TGFbeta) downstream signaling. Given the crucial role of TGFbeta in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.

Methods: CAV1 expression in tissues was analyzed by immunofluorescence and confocal microscopy. The extent of tissue fibrosis in Cav1-knockout mice was assessed by histologic/histochemical analyses and quantified by hydroxyproline assays. Cav1-null and SSc fibroblast phenotypes and protein production were analyzed by real-time polymerase chain reaction, immunofluorescence, Western blot, and multiplexed enzyme-linked immunosorbent assay techniques. The effects of restoration of caveolin 1 function in SSc fibroblasts in vitro were also examined using a cell-permeable recombinant CAV1 peptide.

Results: CAV1 was markedly decreased in the affected lungs and skin of SSc patients. Cav1-knockout mice developed pulmonary and skin fibrosis. Down-regulation of caveolin 1 was maintained in cultured SSc fibroblasts, and restoration of caveolin 1 function in vitro normalized their phenotype and abrogated TGFbeta stimulation through inhibition of Smad3 activation.

Conclusion: Caveolin 1 appears to participate in the pathogenesis of tissue fibrosis in SSc. Restoration of caveolin 1 function by treatment with a cell-permeable peptide corresponding to the CAV1 scaffolding domain may be a novel therapeutic approach in SSc.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Connective Tissue Growth Factor / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibrosis / etiology*
  • Fibrosis / genetics
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Fluorescent Antibody Technique
  • Humans
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Skin / metabolism*
  • Skin / pathology
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • Caveolin 1
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • RNA, Messenger
  • Recombinant Proteins
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor