Potential treatment of keloid pathogenesis with follistatin 288 by blocking the activin molecular pathway

Exp Dermatol. 2021 Mar;30(3):402-408. doi: 10.1111/exd.14223. Epub 2020 Nov 16.

Abstract

Keloids are benign tumours caused by abnormal wound healing driven by increased expression of cytokines, including activin A. This study compared effects of activins on normal and keloid-derived human dermal fibroblasts and investigated a novel treatment for keloids using follistatin. Normal skin and keloid tissue samples from 11 patients were used to develop primary fibroblast cultures, which were compared in terms of their histology and relevant gene (qRT-PCR and RNAseq) and protein (ELISA) expression. Activin A (INHBA) and connective tissue growth factor (CTGF) gene expression were significantly upregulated in keloid fibroblasts, as was activin A protein expression in cell lysates and culture medium. Activator protein 1 inhibitor (SR11302) significantly decreased INHBA and CTGF expression in keloid fibroblasts and a single treatment of follistatin over 5 days significantly inhibited activin and various matrix-related genes in keloid fibroblasts when compared to controls. Follistatin, by binding activin A, suppressed CTGF expression suggesting a novel therapeutic role in managing keloids and perhaps other fibrotic diseases.

Keywords: RNAseq and ELISA; activins; follistatin; gene expression; human dermal fibroblasts; keloid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Elastin / genetics
  • Elastin / metabolism
  • Fibroblasts
  • Follistatin / pharmacology*
  • Gene Expression / drug effects*
  • Humans
  • Inhibin-beta Subunits / antagonists & inhibitors*
  • Inhibin-beta Subunits / genetics
  • Inhibin-beta Subunits / metabolism
  • Inhibin-beta Subunits / pharmacology
  • Interleukin-6 / genetics
  • Keloid / drug therapy
  • Keloid / genetics*
  • Keloid / metabolism*
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Retinoids / pharmacology
  • Up-Regulation

Substances

  • CCN2 protein, human
  • Follistatin
  • IL6 protein, human
  • Interleukin-6
  • Plasminogen Activator Inhibitor 1
  • Retinoids
  • SERPINE1 protein, human
  • SR 11302
  • follistatin, 288-amino acid isoform
  • inhibin beta A subunit
  • Connective Tissue Growth Factor
  • Elastin
  • Inhibin-beta Subunits