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ALK5 inhibition blocks TGFβ-induced CCN1 expression in human foreskin fibroblasts

Katherine Thompson1, Hannah Murphy-Marshman, Andrew Leask

  • 1Department of Dentistry, University of Western Ontario, London, ON, Canada, N6A 5C1.

Journal of Cell Communication and Signaling
|February 26, 2014
PubMed

Insights

Transforming growth factor-beta (TGFβ) regulates connective tissue growth factor (CCN) expression in fibroblasts. Blocking TGFβ signaling via ALK5 inhibition reciprocally controls CCN1 and CCN3, offering potential anti-fibrotic strategies.

Area of Science:

  • Fibroblast biology
  • Cytokine signaling
  • Extracellular matrix regulation

Background:

  • Transforming growth factor-beta (TGFβ) is a potent profibrotic cytokine.
  • Connective tissue growth factor (CCN2/CTGF) is induced by TGFβ in fibroblasts.
  • TGFβ differentially regulates CCN1 and CCN3 expression in various cell types.

Purpose of the Study:

  • To investigate the effect of TGFβ and ALK5 inhibition on CCN1 and CCN3 expression in human foreskin fibroblasts.
  • To clarify the reciprocal regulation of CCN1 and CCN3 by TGFβ signaling.

Main Methods:

  • Treatment of human foreskin fibroblasts with TGFβ.
  • Pharmacological inhibition of TGFβ type I receptor (ALK5) using SB-431542.
  • Analysis of CCN1 and CCN3 gene expression.

Main Results:

  • TGFβ treatment induced CCN1 expression in human foreskin fibroblasts.
  • TGFβ suppressed CCN3 expression in a manner sensitive to SB-431542.
  • These findings demonstrate reciprocal regulation of CCN1 and CCN3 by TGFβ signaling via ALK5.

Conclusions:

  • TGFβ signaling through ALK5 reciprocally regulates CCN1 and CCN3 expression in human foreskin fibroblasts.
  • Targeting ALK5 or increasing CCN3 levels may represent viable anti-fibrotic therapeutic strategies.

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