Inhibition of Putative Hyalurosome Platform in Keratinocytes as a Mechanism for Corticosteroid-Induced Epidermal Atrophy

Abstract

The main limitation of using topical corticosteroids in dermatology is their atrophic effects on the skin. We have previously proposed a molecular platform composed of CD44, EGFR, and hyaluronate synthase (HAS) that is functionally defective in dermatoporosis, a chronic cutaneous insufficiency/fragility syndrome. In this study, we explored the molecular mechanisms of the skin atrophy induced by corticosteroids. We observed an important skin atrophy and a significant decrease of hyaluronic acid (HA), its main cell surface receptor CD44, and F-actin in mouse skin treated with topical clobetasol propionate (CP). Human keratinocytes exposed to CP showed an impaired HA secretion and diminished expression of CD44 and HAS3. CP also abolished filopodia of keratinocytes exposed to CP together with a redistribution of CD44 and F-actin depolymerization. We also show that HA fragments of intermediary size (HAFi) induced keratinocyte filopodia and protected them against CP. Topical HAFi induced hyperplasia in mouse epidermis and prevented CP-induced atrophy. Our results suggest that a CD44/EGFR/HAS platform associated with F-actin and filopodia of keratinocytes is the target of corticosteroids for their atrophogenic effects. These observations may lead to the development of new treatment and prevention strategies for corticosteroid-induced skin atrophy.

575 Senescent atrophic epidermis retains Lrig1+ stem cells and loses Wnt signaling, a phenotype shared with CD44KO mice

“…These two clusters are consistent with in vitro observation on keratinocytes, as CD44 and EGFR are both co-expressed on the top of filopodial protrusions [13]. In addition, Lrig1 silencing tended to induce a strong increase of filopodia as well as an increase in CD44 and HB-EGF expression, which are both involved in filopodia structures and the putative hyalurosome platform [13]. The fact that Lrig1 may be an inhibitor of filopodia structures where EGFR signaling is induced makes sense considering the EGFR-inhibition activity of Lrig1 [30].…”

“…This is consistent with a similar biological activity also described in the intestinal epithelium [11,12]. Cell surface receptor of hyaluronate (HA), CD44, was reported to be crucial for epidermal homeostasis [13]. The importance of CD44 in the epidermis may be related to its role in the putative molecular platform, hyalurosome, where it modulates the activity of EGFR and Factin cytoskeleton [13,14,15].…”

“…At the cutaneous level, the expression of differentiation markers were reported to be disturbed and the assembly of tight-junctions was shown to be impaired [20,28]. A delayed wound healing and hair regrowth was also reported, pointing out a disturbed epidermal homeostasis [13,14,15,21]. It appears that the homeostasis of IFE is abrogated or at least severely impaired in ears of the CD44KO mice.…”

“…Cell surface receptor of hyaluronate (HA), CD44, was reported to be crucial for epidermal homeostasis [13]. The importance of CD44 in the epidermis may be related to its role in the putative molecular platform, hyalurosome, where it modulates the activity of EGFR and Factin cytoskeleton [13,14,15]. CD44 downregulation drives the atrophy in mouse epidermis induced by corticosteroids and is associated with human epidermal atrophy [13,14,16].…”

“…The importance of CD44 in the epidermis may be related to its role in the putative molecular platform, hyalurosome, where it modulates the activity of EGFR and Factin cytoskeleton [13,14,15]. CD44 downregulation drives the atrophy in mouse epidermis induced by corticosteroids and is associated with human epidermal atrophy [13,14,16]. This kind of severe form of epidermal atrophy was described in humans as part of the phenotype of a general syndrome of skin insufficiency associated with aging and topical and systemic corticosteroid treatments, also called dermatoporosis [8,16,17].…”