Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: Importance of hyaluronan for the mitogenic response of PDGF-BB
Résumé
The glycosaminoglycan hyaluronan is important in many tissue repair processes. We have investigated the synthesis of hyaluronan in a panel of cell lines of fibroblastic and epithelial origin in response to platelet-derived growth factor (PDGF)-BB and other growth factors. Human dermal fibroblasts exhibited the highest hyaluronan synthesizing activity in response to PDGF-BB. Analysis of hyaluronan synthase (HAS) and hyaluronidase (HYAL) mRNA expression showed that PDGF-BB treatment induced a 3-fold increase in the already high level of HAS2 mRNA, and increases in HAS1 and HYAL1 mRNA, whereas the levels of HAS3 and HYAL2 mRNA were not affected. Furthermore, PDGF-BB also increased the amount and activity of HAS2 protein, but not of HYAL1 and HYAL2 proteins. Using inhibitors for MEK1/2 (U0126) and for PI3 kinase (LY294002), as well as the SN50 inhibitor, that prevents translocation of the active NFkB to the nucleus, we observed a complete inhibition of both HAS2 transcriptional activity and hyaluronan synthesis, whereas inhibitors of other signaling pathways were without any significant effect. Transforming growth factor-β1 (TGF-β1) did not increase the activity of hyaluronan synthesis in dermal fibroblasts, but increased the activity of HYALs. Importantly, inhibition of hyaluronan binding to its receptor CD44 by the monoclonal antibody Hermes-1, inhibited PDGF-BB-stimulated [ 3}H]thymidine incorporation of dermal fibroblasts. We conclude that the Erk MAP kinase and PI3 kinase signaling pathways are necessary for the regulation of hyaluronan synthesis by PDGF-BB, and that prevention of its binding to CD44 inhibits PDGF-BB-induced cell growth.
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