title: Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism.
abstract: BACKGROUND
  Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeutic options at present.
  
  
  RESULTS
  Atrophic skin displays a decreased hyaluronate (HA) content and expression of the major cell-surface hyaluronate receptor, CD44. In an effort to develop a therapeutic strategy for skin atrophy, we addressed the effect of topical administration of defined-size HA fragments (HAF) on skin trophicity. Treatment of primary keratinocyte cultures with intermediate-size HAF (HAFi; 50,000-400,000 Da) but not with small-size HAF (HAFs; <50,000 Da) or large-size HAF (HAFl; >400,000 Da) induced wild-type (wt) but not CD44-deficient (CD44-/-) keratinocyte proliferation. Topical application of HAFi caused marked epidermal hyperplasia in wt but not in CD44-/- mice, and significant skin thickening in patients with age- or corticosteroid-related skin atrophy. The effect of HAFi on keratinocyte proliferation was abrogated by antibodies against heparin-binding epidermal growth factor (HB-EGF) and its receptor, erbB1, which form a complex with a particular isoform of CD44 (CD44v3), and by tissue inhibitor of metalloproteinase-3 (TIMP-3).
  
  
  CONCLUSIONS
  Our observations provide a novel CD44-dependent mechanism for HA oligosaccharide-induced keratinocyte proliferation and suggest that topical HAFi application may provide an attractive therapeutic option in human skin atrophy.
authors.affiliation: Department of Dermatology, University of Geneva, Geneva, Switzerland. gkaya@hcuge.ch
authors.forename: Gürkan
authors.initials: G
authors.lastname: Kaya
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
mesh_terms: D000328:Adult; D000818:Animals; D001284:Atrophy; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D047468:Immunoprecipitation; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009844:Oligosaccharides / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014746:Vimentin / Q000378:metabolism
chemical_list: D000091344:Filaggrin Proteins; D018960:Hyaluronan Receptors; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D009844:Oligosaccharides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014746:Vimentin; C064554:loricrin; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid; D066246:ErbB Receptors