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.
Several hydroxyproline (Hyp)-containing food-derived collagen peptides were identified in human blood after oral ingestion of gelatin hydrolysates. However, these types of peptides were not quantified in human plasma. In this report, a sensitive LC-MS/MS method was introduced for simultaneous quantitative analysis of Hyp-containing peptides. All peptide concentrations were determined accurately, with all coefficients of determination (r(2)) >0.999. The method achieved detection and quantification limits of 0.01 pmol/ml and 12.5-1,000 pmol/ml in plasma, respectively. Concentrations were quantified for nine Hyp-containing peptides in human plasma by this method, identifying Pro-Hyp (C(max) = 60.65 +/- 5.74 nmol/ml) as the major constituent of food-derived collagen peptides, while the minor components were Ala-Hyp-Gly, Ser-Hyp-Gly, Ala-Hyp, Phe-Hyp, Leu-Hyp, Ile-Hyp, Gly-Pro-Hyp, and Pro-Hyp-Gly (C(max) from 23.84 to 0.67 nmol/ml). Thus a total of nine Hyp-containing peptides in human plasma were successfully quantified by this approach. The concentration of Hyp-containing peptides is substantially higher than that following oral administration of other peptides.
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