Tiina Jokela Regulation of Hyaluronan Synthesis by UDP - sugars Tiina Jokela Regulation of Hyaluronan Synthesis by UDP - sugars

Hyaluronan is a large glycosaminoglycan consisting of alternating Nacetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) units. It is synthesized by hyaluronan synthase enzymes (HAS1,2,3). In many tissues hyaluronan is a major component of the extracellular matrix. It enhances cell proliferation, migration, and controls differentiation. High hyaluronan levels are associated with cancer progression and inflammation. In this study a new inhibitor of the hyaluronan synthesis, mannose, was discovered and it was demonstrated that it depletes content of UDP-GlcNAc. The three HAS enzymes showed different sensitivities to the cellular content of the UDPGlcNAc. HAS3 had the highest affinity to the precursors and HAS1 the lowest, suggesting that the HAS-isoenzyme distribution in a particular cell type determines the sensitivity of its hyaluronan synthesis to UDP-sugar supply. Interestingly, a feedback mechanism from UDP-sugar content to HAS2 expression was found since fluctuations in UDP-GlcNAc content caused reciprocal changes in HAS2 transcription. This regulation is likely mediated by O-GlcNAc modifications of transcription factors YY1 and SP1. This study also showed that the hyaluronan-dependent binding of leukocytes can be induced by the inflammatory mediators and cell stress, and inhibited with mannose. In an in vivo wound model mannose reduced the hyaluronan level, granulation tissue growth and accumulation of leukocytes. Altogether, this work shows that cellular UDP-sugar content regulates hyaluronan synthesis and hyaluronan-mediated functions, such as cell migration, proliferation, and leukocyte adhesion. Therefore, inhibition of hyaluronan synthesis by reduction of UDP-GlcNAc using mannose or similar effectors may provide novel ways to treat pathological processes that involve excessive hyaluronan production, e.g. in inflammation and cancer. National Library of Medical Classification: Medical Subject Headings: Hyaluronan, UDP-sugars, inflammation