Collagen-derived dipeptide, proline-hydroxyproline, stimulates cell proliferation and hyaluronic acid synthesis in cultured human dermal fibroblasts

J Dermatol. 2010 Apr;37(4):330-8. doi: 10.1111/j.1346-8138.2010.00827.x.


Orally ingested collagen undergoes degradation to small di- or tripeptides, which are detected in circulating blood 2 h after ingestion. The influence of collagen-derived peptides on dermal extracellular matrix components and cell proliferation was studied using cultured human dermal fibroblasts. Of the various collagenous peptides tested here, the dipeptide proline-hydroxyproline (Pro-Hyp) enhanced cell proliferation (1.5-fold) and hyaluronic acid synthesis (3.8-fold) at a dose of 200 nmol/mL. This was concomitant with a 2.3-fold elevation of hyaluronan synthase 2 (HAS2) mRNA levels. Small interfering RNA (siRNA)-mediated knockdown of the HAS2 gene in human dermal fibroblasts inhibited Pro-Hyp-induced HAS2 mRNA transcription and cell mitotic activity. Addition of genistein or H7, a protein kinase inhibitor, abolished the Pro-Hyp-induced HAS2 mRNA stimulation. Pro-Hyp elevated phosphorylation of signal transducer and activator of transcription 3 (STAT3) within a short time period (60 min). These results suggest that Pro-Hyp stimulates both cell mitotic activity and hyaluronic acid synthesis, which is mediated by activation of HAS2 transcription.

MeSH terms

  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Collagen / metabolism*
  • Dermis / cytology
  • Dermis / drug effects*
  • Dermis / metabolism
  • Dipeptides / metabolism
  • Dipeptides / pharmacology*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Genistein / pharmacology
  • Glucuronosyltransferase / antagonists & inhibitors
  • Glucuronosyltransferase / genetics
  • Humans
  • Hyaluronan Synthases
  • Hyaluronic Acid / biosynthesis*
  • Protein Kinase Inhibitors / pharmacology
  • STAT3 Transcription Factor / metabolism
  • Transcription, Genetic / physiology


  • Dipeptides
  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • prolyl-4-hydroxyproline
  • Hyaluronic Acid
  • Collagen
  • Genistein
  • Glucuronosyltransferase
  • HAS2 protein, human
  • Hyaluronan Synthases