TGF-beta signal transduction in corneal wound healing as a therapeutic target

Cornea. 2004 Nov;23(8 Suppl):S25-30. doi: 10.1097/01.ico.0000136668.41000.73.


This article reviews recent progress in research on the role of Smad signaling in corneal wound healing. Smad2 and Smad3 are key signaling molecules downstream of the cell surface receptor of transforming growth factor-beta (TGF-beta) or activin. On ligand binding to the receptor, Smads2/3 undergo phosphorylation, form complexes with Smad4, and thence convey signaling. TGF-beta isoforms have been detected in corneal epithelium and are also deposited in wounded stroma, suggesting their participation in the wound-healing process in corneal tissue. Human or mouse uninjured healthy corneal epithelium shows nuclear accumulation of Smads3/4, indicating active Smad signaling in this tissue. Migrating corneal epithelium lacks nuclear Smad accumulation with up-regulation of Smad7, but p38MAPK is activated. Organ-culture experiments show that p38MAPK activation depends on endogenous TGF-beta and that activation of p38MAPK results in cell proliferation cessation with a reduction of Erk activation and acceleration of cell migration in healing corneal epithelium. These findings indicate that during healing of corneal epithelial defects, endogenous TGF-beta activates p38MAPK for cell migration and suppression of cell proliferation and up-regulates Smad7 for inhibition of Smad2 and Smad3 signaling, resulting in rapid initial resurfacing of the epithelium. Such involvement of p38MAPK in cell migration has been reported in many cell types and observed in keratocyte culture. Possible benefits of preserving non-Smad cascades in treating problems in corneal wound healing by manipulating TGF-beta signals have been suggested.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Movement / physiology
  • DNA-Binding Proteins / metabolism
  • Epithelium, Corneal / injuries
  • Epithelium, Corneal / physiology*
  • Humans
  • Mice
  • Phosphorylation
  • Signal Transduction / physiology*
  • Smad Proteins
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / physiology*
  • Wound Healing / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • DNA-Binding Proteins
  • Smad Proteins
  • Trans-Activators
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases