Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism.
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.
Kaya
Gürkan
G
Department of Dermatology, University of Geneva, Geneva, Switzerland. gkaya@hcuge.ch
Tran
Christian
C
Sorg
Olivier
O
Hotz
Raymonde
R
Grand
Denise
D
Carraux
Pierre
P
Didierjean
Liliane
L
Stamenkovic
Ivan
I
Saurat
Jean-Hilaire
JH
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
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