Regulation of Hyaluronan Synthesis by UDP-sugars

Hyaluronan is a large glycosaminoglycan composed of alter­ nating units of N­acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA). Hyaluronan is synthesized by hyaluronan syn­ thase enzymes (HAS1,2,3). In many tissues hyaluronan is a major component of the extracellular matrix. It enhances cell proliferation and migration, and controls differentia­ tion. High levels of hyaluronan are associated with cancer progression and inflammation. In this study a new inhibitor of hyaluronan synthesis, mannose, was discovered and it was demonstrated that this depletes UDP­GlcNAc content. The three HAS enzymes showed different sensitivities to the cel­ lular content of UDP­GlcNAc. HAS3 had the highest affinity with the precursors and HAS1 the lowest, suggesting that the HAS­isoenzyme distribution in a particular cell type deter­ mines the sensitivity of its hyaluronan synthesis to UDP­sugar supply. Interestingly, a feedback mechanism from UDP­sugar content to HAS2 expression was found, since fluctuations in UDP­GlcNAc content caused reciprocal changes in HAS2 tran­ scription. This regulation is probably mediated by O­GlcNAc modifications of transcription factors YY1 and SP1. This study also showed that hyaluronan­dependent binding of leukocytes can be induced by inflammatory mediators and cell stress, and inhibited by mannose. In an in vivo wound model mannose reduced hyaluronan level, granulation tissue growth and ac­ cumulation of leukocytes. Altogether, this work showed that cellular UDP­sugar content regulates hyaluronan synthesis and hyaluronan­mediated functions, such as cell migration, proliferation, and leukocyte adhesion. Therefore, inhibition of hyaluronan synthesis by a reduction in UDP­GlcNAc, us­ ing mannose or similar effectors, may provide novel ways to treat pathological processes that involve excessive hyaluronan production, e.g. inflammation and cancer.