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 ∼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 ∼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. We found that d-mannose dose-dependently decreases hyaluronan synthesis in cultured epidermal keratinocytes 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 ∼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. Hyaluronan is a ubiquitous glycosaminoglycan present in variable concentrations in the pericellular and extracellular matrix of vertebrate tissues. The general functions most frequently associated with hyaluronan are extracellular matrix organization (1Laurent T.C. Laurent U.B. Fraser J.R. Immunol. Cell Biol. 1996; 74: A1-A7Crossref PubMed Scopus (396) Google Scholar) and adhesion, migration and proliferation of cells (2Pienimäki J.P. Rilla K. Fulop C. Sironen R.K. Karvinen S. Pasonen S. Lammi M.J. Tammi R. Hascall V.C. Tammi M.I. 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Hyaluronan synthases (HAS1–3), 2The abbreviations used are: HAShyaluronan synthase4-MU4-methylumbelliferoneELSAenzyme-linked sorbent assayGlcN-1Pglucosamine 1-phosphateGlcN-6Pglucosamine 6-phosphateGFATglutamine:fructose-6-phosphate amidotransferasesGPIglucosamine-6-phosphate isomeraseHABChyaluronan binding complex of the and epidermal mass a of vertebrate are in the membrane and the growing glycosaminoglycan the extracellular The UDP-glucuronic and UDP-N-acetylglucosamine as to the hyaluronan up to with the B.P. Tammi M.I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). Hyaluronan synthesis is known to the of K. Pasonen-Seppänen S. Tammi R. Tammi M.I. C. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar), which is by and (2Pienimäki J.P. Rilla K. Fulop C. Sironen R.K. Karvinen S. Pasonen S. Lammi M.J. Tammi R. Hascall V.C. Tammi M.I. J. Biol. 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Sironen R.K. Karvinen S. Pasonen S. Lammi M.J. Tammi R. Hascall V.C. Tammi M.I. J. Biol. Chem. 2001; 276: 20428-20435Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). The inhibition occurred introduction of mannose, because the in the was as as the the synthesis of was not in the and The of in hyaluronan synthesis in cells been associated with in (2Pienimäki J.P. Rilla K. Fulop C. Sironen R.K. Karvinen S. Pasonen S. Lammi M.J. Tammi R. Hascall V.C. Tammi M.I. J. Biol. Chem. 2001; 276: 20428-20435Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 3Karvinen S. Pasonen-Seppänen S. Hyttinen J.M. Pienimäki J.P. Törrönen K. Jokela T.A. Tammi M.I. Tammi R. J. Biol. Chem. 2003; 278: 49495-49504Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, S. Karvinen S. Törrönen K. Hyttinen J.M. Jokela T. Lammi M.J. Tammi M.I. Tammi R. J. Investig. 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Mannose reduced the UDP-HexNAc in a with the of ∼50%, whereas the was increased glucose, galactose, and fructose did not in the intracellular of UDP-HexNAc or not The reduction in UDP-HexNAc had occurred by h following introduction of 20 mm mannose with the effect on hyaluronan synthesis and indicating a UDP-HexNAc in UDP-HexNAc and Hyaluronan and the by that mannose reduced the of the UDP-HexNAc that its is the or of This was by the with glucosamine together with mannose, because glucosamine is to the in the of of glucosamine not the inhibition by mannose on the UDP-HexNAc content but an as with controls The of increased hyaluronan synthesis was increased by mannose was present or not The of and that and not by 2 h of with mannose not that was not the influence of mannose was not because of a general inhibition of synthesis as by the of not The the mannose reduced the of for and cellular concentration of UDP-HexNAc hyaluronan synthesis. but the of Hyaluronan by the of hyaluronan synthesis to the reduced concentration of as the effect of mannose with that of which has been to its effect on hyaluronan synthesis by a reduction of to 14% of was found by whereas the of was reduced to The influence of was its effect 3 h of and mannose, which reductions in the and for possible additive Mannose and together a of both UDP-HexNAc and as expected and the synthesis of and h was to a by the of the with no additive effect and This that of the can and the synthesis of Mannose and is involved in keratinocyte functions as migration, and wound healing (5Tammi R. 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The inhibition was not because of its on the of the culture medium or general in the of the cells, because of mannose, including glucose, galactose, and had no effect. Mannose was not and its effect on hyaluronan synthesis was of studies that in hyaluronan synthesis are by in the of of or more of the (2Pienimäki J.P. Rilla K. Fulop C. Sironen R.K. Karvinen S. Pasonen S. Lammi M.J. Tammi R. Hascall V.C. Tammi M.I. J. Biol. Chem. 2001; 276: 20428-20435Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 3Karvinen S. Pasonen-Seppänen S. Hyttinen J.M. Pienimäki J.P. Törrönen K. Jokela T.A. Tammi M.I. Tammi R. J. Biol. Chem. 2003; 278: 49495-49504Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, K. Pasonen-Seppänen S. Tammi R. Tammi M.I. C. J. Biol. 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