Heparin-binding epidermal-growth-factor-like growth factor activation of keratinocyte erbB receptors mediates epidermal hyperplasia, a prominent side-effect of retinoid therapy

James Varani, Mary Zeigler, Michael K. Dame, Sewon Kang, Gary J. Fisher, John J. Voorhees, Stefan W. Stoll, James T. Elder

Research output: Contribution to journalArticlepeer-review

Abstract

Sun-protected human skin was maintained in organ culture and treated with all-trans retinoic acid in the presence or absence of reversible or irreversible pharmacologic antagonists of c-erbB receptor tyrosine kinase activity. In the absence of these inhibitors, all-trans retinoic acid induced epidermal hyperplasia comparable to that induced in intact skin by all-trans retinol or all-trans retinoic acid itself. There was a strong correlation between inhibition of epidermal hyperplasia in organ culture and inhibition of epidermal-growth-factor-dependent keratinocyte growth in monolayer culture. In additional studies it was shown that all-trans retinoic acid could overcome the known inhibitory effects of calcium on expression of HB-EGF-like growth factor mRNA in organ-cultured skin. Further, it was shown that an antibody to HB-EGF-like growth factor inhibited retinoid-stimulated epidermal hyperplasia in organ culture and reduced proliferation in cultured keratinocytes. In contrast, the c-erbB receptor tyrosine kinase antagonists and the neutralizing HB-EGF-like growth factor antibody were ineffective in inhibiting all-trans-retinoic-acid-dependent survival and proliferation of human dermal fibroblasts. Taken together, these data indicate (i) that retinoid-induced epidermal hyperplasia in human skin proceeds through c-erbB, and (ii) that HB-EGF-like growth factor is one of the c-erbB ligands mediating this effect.

Original languageEnglish (US)
Pages (from-to)1335-1341
Number of pages7
JournalJournal of Investigative Dermatology
Volume117
Issue number6
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • EGF-like growth factor
  • Epidermal growth factor receptor
  • Heparin-binding
  • Human skin organ culture
  • Retinoic acid
  • c-erbB

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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