title: Synergistic effect of hyaluronate fragments in retinaldehyde-induced skin hyperplasia which is a Cd44-dependent phenomenon.
abstract: BACKGROUND
  CD44 is a polymorphic proteoglycan and functions as the principal cell-surface receptor for hyaluronate (HA). Heparin-binding epidermal growth factor (HB-EGF) activation of keratinocyte erbB receptors has been proposed to mediate retinoid-induced epidermal hyperplasia. We have recently shown that intermediate size HA fragments (HAFi) reverse skin atrophy by a CD44-dependent mechanism.
  
  
  RESULTS
  Treatment of primary mouse keratinocyte cultures with retinaldehyde (RAL) resulted in the most significant increase in keratinocyte proliferation when compared with other retinoids, retinoic acid, retinol or retinoyl palmitate. RAL and HAFi showed a more significant increase in keratinocyte proliferation than RAL or HAFi alone. No proliferation with RAL was observed in CD44-/- keratinocytes. HA synthesis inhibitor, 4-methylumbelliferone inhibited the proliferative effect of RAL. HB-EGF, erbB1, and tissue inhibitor of MMP-3 blocking antibodies abrogated the RAL- or RAL- and HAFi-induced keratinocyte proliferation. Topical application of RAL or RAL and HAFi for 3 days caused a significant epidermal hyperplasia in the back skin of wild-type mice but not in CD44-/- mice. Topical RAL and HAFi increased epidermal CD44 expression, and the epidermal and dermal HA. RAL induced the expression of active HB-EGF and erbB1. However, treatment with RAL and HAFi showed a more significant increase in pro-HB-EGF when compared to RAL or HAFi treatments alone. We then topically applied RAL and HAFi twice a day to the forearm skin of elderly dermatoporosis patients. After 1 month of treatment, we observed a significant clinical improvement.
  
  
  CONCLUSIONS
  Our results indicate that (i) RAL-induced in vitro and in vivo keratinocyte proliferation is a CD44-dependent phenomenon and requires the presence of HA, HB-EGF, erbB1 and MMPs, (ii) RAL and HAFi show a synergy in vitro and in vivo in mouse skin, and (iii) the combination of RAL and HAFi seems to have an important therapeutic effect in dermatoporosis.
authors.affiliation: Department of Dermatology, University of Geneva, Geneva, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Barnes
authors.forename: Christian
authors.initials: C
authors.lastname: Tran
authors.forename: Olivier
authors.initials: O
authors.lastname: Sorg
authors.forename: Raymonde
authors.initials: R
authors.lastname: Hotz
authors.forename: Denise
authors.initials: D
authors.lastname: Grand
authors.forename: Pierre
authors.initials: P
authors.lastname: Carraux
authors.forename: Liliane
authors.initials: L
authors.lastname: Didierjean
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
authors.forename: Jean-Hilaire
authors.initials: JH
authors.lastname: Saurat
authors.forename: Gürkan
authors.initials: G
authors.lastname: Kaya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001284:Atrophy; D004817:Epidermis / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry*; D006965:Hyperplasia / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008875:Middle Aged; D012172:Retinaldehyde / Q000494:pharmacology*; D012871:Skin Diseases / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D012172:Retinaldehyde