Pharmacological impacts of Mucopolysacccharide Polyphosphates in skin involves inhibition of Amphiregulin-mediated signals in keratinocytes

The epidermis, the most superficial layer of human skin, serves a critical barrier function, protecting the body from external pathogens and allergens. Dysregulation in the epidermal differentiation process contributes to barrier dysfunction and is implicated in the pathology of various dermatological diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulfate (MPS) is used as a moisturizing agent for xerosis in AD patients. However, its mechanism of action on keratinocytes, the main constituent of the epidermis, remains unclear. In this study, we investigated the impact of MPS on keratinocytes by subjecting adult human epidermal keratinocyte (HEKa) cells and three-dimensional cultured keratinocytes to MPS treatment, followed by transcriptome analysis. The analysis revealed that MPS treatment enhances keratinocyte differentiation and suppresses proliferation. We focused on amphiregulin (AREG), a membrane protein that belongs to the epidermal growth factor (EGF) family and possesses a heparin-binding domain, as a significant target of the MPS among the genes altered by MPS. It is revealed that MPS exerts an inhibitory effect directly on AREG, rather than on the EGF receptor or other members of the EGF family. Furthermore, it is suggested that AREG leads to a reduction in epidermal barrier function, whereas MPS contributes to barrier enhancement through AREG inhibition. Collectively, these findings suggest that MPS modulates barrier function through the inhibition of AREG, offering insights into potential therapeutic strategies for skin barrier restoration.