Abstract
Chondroitin sulfates are implicated in epidermal biology, but functional significance of chondroitin sulfates remains unclear. Here, we report that chondroitin 6-sulfate is important for the maintenance of epidermal homeostasis. Mice deficient in chondroitin 6-O-sulfotransferase-1 (C6st-1), which is involved in biosynthesis of chondroitin 6-sulfate, exhibited keratinocyte hyperproliferation and impaired skin permeability barrier function. Chondroitin 6-sulfate directly interacted with the EGF receptor and negatively controlled ligand-induced EGF receptor signaling. Normal function of hyperproliferative C6st-1-knockout mouse-derived keratinocytes was rescued by treatment with exogenous chondroitin 6-sulfate. Epidermal hyperplasia, induced using imiquimod, was more severe in C6st-1-knockout mice than in C6st-1 wild-type mice. Taken together, these findings indicate that chondroitin 6-sulfate represses keratinocyte proliferation in normal skin, and that the expression level of C6st-1 may be associated with susceptibility to psoriasis.
Highlights
Chondroitin sulfates are implicated in epidermal biology, but functional significance of chondroitin sulfates remains unclear
All mice produced similar amounts of chondroitin sulfate (CS), while production of the C and D units was decreased in chondroitin 6-O-sulfotransferase-1 (C6st-1) wild type (WT), C6st-1 hetero (HE), and C6st-1 knockout (KO) mice with respect to genotype (Fig. 1d, e, Supplementary Table 1)
Immunohistochemical analysis using anti-chondroitin sulfate C (CS-C) antibody demonstrated that CS-C was expressed beneath the keratin 14 (K14)-positive stem cells of epidermal basal layer (Fig. 1g)
Summary
Chondroitin sulfates are implicated in epidermal biology, but functional significance of chondroitin sulfates remains unclear. Epidermal hyperplasia, induced using imiquimod, was more severe in C6st-1-knockout mice than in C6st[1] wild-type mice Taken together, these findings indicate that chondroitin 6-sulfate represses keratinocyte proliferation in normal skin, and that the expression level of C6st-1 may be associated with susceptibility to psoriasis. The inner basal layer adheres to an underlying basement membrane, which is rich in extracellular matrix components containing chondroitin sulfate (CS) proteoglycans This layer contains proliferative keratinocytes that are typed by their expression of genes encoding keratins 5 and 14, and growth factor receptors such as the EGF receptor (EGFR)[1]. Koike et al reported that FAM20B regulates the sulfation profile of CS chains and total amount of CS synthesized in cells[3] Based on these findings, we hypothesized that a decrease in the expression of FAM20B would impact CS biosynthesis and would be associated with psoriasis
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