Mannose inhibits hyaluronan synthesis by down-regulation of the cellular pool of UDP-N-acetylhexosamines

We found that D-mannose dose-dependently decreases hyaluronan synthesis in cultured epidermal keratinocytes to similar to 50%, whereas glucose, galactose, and fructose up to 20 mM concentration had no effect. The full inhibition occurred within 3 h following introduction of mannose and did not involve down-regulation of hyaluronan synthase (Has1 - 3) mRNA. Following introduction of mannose, there was an similar to 50% reduction in the cellular concentration of UDP-N-acetylhexosamines (UDP-HexNAc, i. e. UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine). On the other hand, 2 mM glucosamine in the culture medium increased UDP-HexNAc content, stimulated hyaluronan secretion, and negated the effect of mannose, supporting the notion that the inhibition by mannose on hyaluronan synthesis was because of down-regulated UDP-HexNAc content. The content of UDP-glucuronic acid, the other building block for hyaluronan synthesis, was not reduced by mannose but declined from 39 to 14% of controls by 0.2-1.0 mM 4-methylumbelliferone, another compound that inhibits hyaluronan synthesis. Applying 4-methylumbelliferone and mannose together produced the expected reductions in both UDP sugars but no additive reduction in hyaluronan production, indicating that the concentration of each substrate alone can limit hyaluronan synthesis. Mannose is a potentially useful tool in studies on hyaluronan-dependent cell functions, as demonstrated by reduced rates of keratinocyte proliferation and migration, functions known to depend on hyaluronan synthesis.