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

Kana Marunaka,Makiko Goto,Yuji Katsuta,Yuta Yoshino,Akira Ikari,Mao Kobayashi,Shokoku Shu

doi:10.3390/ijms23010071

Abstract

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.

Highlights

Autosomal recessive congenital ichthyosis (ARCI) is a debilitating skin disease characterized by aberrant barrier function and diffuse skin scaling
The mRNA levels of HAS2/3 were significantly increased in 5.8 mM MgCl2 medium compared with 0.8 mM MgCl2 medium, whereas they were decreased in 0 mM MgCl2 medium (Figure 1A)
The MgCl2 supplementation-induced elevation of fluorescence intensity was significantly inhibited by nonimprinted in Prader-Willi/Angelman syndrome-like domain-containing 4 (NIPAL4) knockdown. These results indicate that NIPA4 may function as Mg 2+ channel in mentation-induced elevation of fluorescence intensity was significantly inhibited by NIHaCaT

Summary

Introduction

Autosomal recessive congenital ichthyosis (ARCI) is a debilitating skin disease characterized by aberrant barrier function and diffuse skin scaling. ARCI can be clinically divided into three types, including harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE) [1]. ARCI associated with the mutation of the adenosine triphosphate (ATP) binding cassette subfamily A member 12 (ABCA12) gene. Mutations in various genes including ABCA12, transglutaminase 1 (TGM1), nonimprinted in Prader-Willi/Angelman syndrome-like domain-containing 4 (NIPAL4), 3-lipoxygenase (ALOXE3), 12-lipoxygenase (ALOX12B), CYP4F22, and loci on 12p11.2-q13 are implicated in the pathogenesis of LI and CIE. NIPAL4, known as ichthyin, codes for putative magnesium transporter NIPA4, which is composed of several transmembrane domains.

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Conclusion