A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice

J Clin Invest. 2011 Nov;121(11):4348-61. doi: 10.1172/JCI46475. Epub 2011 Oct 24.

Abstract

Wounds that fail to heal in a timely manner, for example, diabetic foot ulcers, pose a health, economic, and social problem worldwide. For decades, conventional wisdom has pointed to growth factors as the main driving force of wound healing; thus, growth factors have become the center of therapeutic developments. To date, becaplermin (recombinant human PDGF-BB) is the only US FDA-approved growth factor therapy, and it shows modest efficacy, is costly, and has the potential to cause cancer in patients. Other molecules that drive wound healing have therefore been sought. In this context, it has been noticed that wounds do not heal without the participation of secreted Hsp90α. Here, we report that a 115-aa fragment of secreted Hsp90α (F-5) acts as an unconventional wound healing agent in mice. Topical application of F-5 peptide promoted acute and diabetic wound closure in mice far more effectively than did PDGF-BB. The stronger effect of F-5 was due to 3 properties not held by conventional growth factors: its ability to recruit both epidermal and dermal cells; the fact that its ability to promote dermal cell migration was not inhibited by TGF-β; and its ability to override the inhibitory effects of hyperglycemia on cell migration in diabetes. The discovery of F-5 challenges the long-standing paradigm of wound healing factors and reveals a potentially more effective and safer agent for healing acute and diabetic wounds.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Topical
  • Animals
  • Becaplermin
  • Cells, Cultured
  • Diabetes Complications / drug therapy
  • Diabetes Complications / physiopathology
  • HSP90 Heat-Shock Proteins / administration & dosage
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / pharmacology*
  • HSP90 Heat-Shock Proteins / physiology
  • Humans
  • Mice
  • Mice, Hairless
  • Mice, Nude
  • Models, Biological
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology
  • Peptide Fragments / physiology
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-sis
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Wound Healing / drug effects*
  • Wound Healing / physiology

Substances

  • HSP90 Heat-Shock Proteins
  • HSP90alpha protein, human
  • Peptide Fragments
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Recombinant Proteins
  • Becaplermin