Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism

PLoS Med. 2006 Dec;3(12):e493. doi: 10.1371/journal.pmed.0030493.


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.

Methods and findings: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Atrophy
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism
  • Female
  • Filaggrin Proteins
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / metabolism
  • Hyaluronic Acid / pharmacology*
  • Immunoprecipitation
  • Intermediate Filament Proteins / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Oligosaccharides / pharmacology
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Skin / drug effects
  • Skin / metabolism
  • Skin / pathology
  • Skin Diseases / drug therapy*
  • Skin Diseases / metabolism
  • Skin Diseases / pathology
  • Vimentin / metabolism


  • Filaggrin Proteins
  • Hyaluronan Receptors
  • Intermediate Filament Proteins
  • Membrane Proteins
  • Oligosaccharides
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vimentin
  • loricrin
  • Epidermal Growth Factor
  • Hyaluronic Acid
  • ErbB Receptors