Mechanisms for induction of hyaluronan synthesis and CD44 expression in human skin fibroblasts by PDGF-BB

4502 The molecular mechanisms through which platelet-derived growth factor-BB (PDGF-BB) affects the synthesis of hyaluronan in human skin fibroblast cultures were investigated. Using specific inhibitors of intracellular signaling pathways, we conclude that MEK1/2, PI3K and NFkB are crucial for the stimulation of hyaluronan synthesis by PDGF-BB. This stimulatory effect was mediated by an up-regulation of HAS2 and, to a lesser extent, HAS1 genes which encode hyaluronan synthesizing enzymes; the expression of the HAS3 gene, as well as the HYAL1 and HYAL2 genes which encode hyaluronan degradative enzymes, were not affected by PDGF-BB. In a separate series of experiments, the role of hyaluronan in PDGF-BB-stimulated migration of human skin fibroblasts was investigated. After wounding of a confluent cell culture, PDGF-BB enhanced the cell migration in a hyaluronan-independent, but CD44-dependent manner. Furthermore, PDGF-BB stimulated fibroblasts exhibited an up-regulated CD44 expression in lamellipodial membrane protrusions. Our data suggest that PI3K or MEK1/2 pathways are involved in PDGF-BB-induced increase of hyaluronan synthesis, and that PDGF-BB most likely exerts control over CD44 localization.