Collagen-derived dipeptide, proline-hydroxyproline, stimulates cell proliferation and hyaluronic acid synthesis in cultured human dermal fibroblasts.
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.
Ohara
Hiroki
H
Food and Health R&D Laboratories, Meiji Seika Kaisha, Saitama, Japan. hiroki_ohara@meiji.co.jp
Ichikawa
Satomi
S
Matsumoto
Hitoshi
H
Akiyama
Minoru
M
Fujimoto
Norihiro
N
Kobayashi
Takashi
T
Tajima
Shingo
S
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
D004151:Dipeptides; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C533879:prolyl-4-hydroxyproline; D006820:Hyaluronic Acid; D003094:Collagen; D019833:Genistein; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases