Elevation of Hyaluronan Synthase by Magnesium Supplementation Mediated through the Activation of GSK3 and CREB in Human Keratinocyte-Derived HaCaT Cells

Int J Mol Sci. 2021 Dec 22;23(1):71. doi: 10.3390/ijms23010071.


Skin barrier damage is present in the patients with hereditary disorders of the magnesium channel, but the molecular mechanism has not been fully understood. We found that the expressions of hyaluronan synthase (HAS), HAS2 and HAS3 are influenced by MgCl2 concentration in human keratinocyte-derived HaCaT cells. The exposure of cells to a high concentration (5.8 mM) of MgCl2 induced the elevation of HAS2/3 expression, which was inhibited by mRNA knockdown of nonimprinted in Prader-Willi/Angelman syndrome-like domain containing 4 (NIPAL4). Similarly, the content of hyaluronic acid (HA) was changed according to MgCl2 concentration and the expression of NIPAL4. The MgCl2 supplementation increased the reporter activities of HAS2/3, which were inhibited by NIPAL4 knockdown, indicating that the expressions of HAS2/3 are up-regulated at the transcriptional level. The reporter activities and mRNA levels of HAS2/3, and the production of HA were inhibited by CHIR-99021, a glycogen synthase kinase-3 (GSK3) inhibitor, and naphthol AS-E, a cyclic AMP-response element binding protein (CREB) inhibitor. Furthermore, the mutation in putative CREB-binding sites of promoter region in HAS2/3 genes inhibited the MgCl2 supplementation-induced elevation of promoter activity. Our results indicate that the expressions of HAS2/3 are up-regulated by MgCl2 supplementation in HaCaT cells mediated through the activation of GSK3 and CREB. Magnesium may play a pivotal role in maintaining the skin barrier function and magnesium supplementation may be useful to enhance moisturization and wound repair in the skin.

Keywords: hyaluronan synthase; hyaluronic acid; magnesium.

MeSH terms

  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dietary Supplements
  • Glycogen Synthase Kinase 3 / metabolism*
  • HaCaT Cells
  • Humans
  • Hyaluronan Synthases / metabolism*
  • Hyaluronic Acid / metabolism
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism
  • Magnesium / pharmacology*
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Skin / drug effects
  • Skin / metabolism
  • Up-Regulation / drug effects


  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • RNA, Messenger
  • Hyaluronic Acid
  • Hyaluronan Synthases
  • Glycogen Synthase Kinase 3
  • Magnesium