Abstract
BackgroundCD44 is a polymorphic proteoglycan and functions as the principal cell-surface receptor for hyaluronate (HA). Heparin-binding epidermal growth factor (HB-EGF) activation of keratinocyte erbB receptors has been proposed to mediate retinoid-induced epidermal hyperplasia. We have recently shown that intermediate size HA fragments (HAFi) reverse skin atrophy by a CD44-dependent mechanism.Methodology and Principal FindingsTreatment of primary mouse keratinocyte cultures with retinaldehyde (RAL) resulted in the most significant increase in keratinocyte proliferation when compared with other retinoids, retinoic acid, retinol or retinoyl palmitate. RAL and HAFi showed a more significant increase in keratinocyte proliferation than RAL or HAFi alone. No proliferation with RAL was observed in CD44−/− keratinocytes. HA synthesis inhibitor, 4-methylumbelliferone inhibited the proliferative effect of RAL. HB-EGF, erbB1, and tissue inhibitor of MMP-3 blocking antibodies abrogated the RAL- or RAL- and HAFi-induced keratinocyte proliferation. Topical application of RAL or RAL and HAFi for 3 days caused a significant epidermal hyperplasia in the back skin of wild-type mice but not in CD44−/− mice. Topical RAL and HAFi increased epidermal CD44 expression, and the epidermal and dermal HA. RAL induced the expression of active HB-EGF and erbB1. However, treatment with RAL and HAFi showed a more significant increase in pro-HB-EGF when compared to RAL or HAFi treatments alone. We then topically applied RAL and HAFi twice a day to the forearm skin of elderly dermatoporosis patients. After 1 month of treatment, we observed a significant clinical improvement.Conclusions and SignificanceOur results indicate that (i) RAL-induced in vitro and in vivo keratinocyte proliferation is a CD44-dependent phenomenon and requires the presence of HA, HB-EGF, erbB1 and MMPs, (ii) RAL and HAFi show a synergy in vitro and in vivo in mouse skin, and (iii) the combination of RAL and HAFi seems to have an important therapeutic effect in dermatoporosis.
Highlights
CD44 is a facultative cell surface proteoglycan expressed as several isoforms [1,2] and the principal cell surface receptor of hyaluronate [3,4] (HA), the major component of the extracellular matrix [5]
We have shown that topically applied HAF of intermediate size (HAFi) traverse the skin and induce a CD44-dependent biological effect characterized by a skin regeneration in mice and elderly human patients showing dermatoporosis, the holistic word for human skin fragility and an emerging clinical problem due to chronological aging, longterm sun exposure and chronic use of corticosteroids [15,16,17]
To address the possibility that RAL and HAFi may have a synergy on keratinocyte proliferation and epidermal hyperplasia, we examined the effect of the combination of HAFi and RAL on the mouse skin in vitro and in vivo, and on atrophic skin of elderly patients with dermatoporosis
Summary
CD44 is a facultative cell surface proteoglycan expressed as several isoforms [1,2] and the principal cell surface receptor of hyaluronate [3,4] (HA), the major component of the extracellular matrix [5]. We have recently shown that the epidermal hyperplasia induced by topical retinoids was accompanied by an increased expression of CD44 and hyaluronate synthases and associated with an increase in epidermal and dermal HA in mouse skin [7]. We have shown that the decrease of the expression of CD44 and hyaluronate induced by UVA and UVB in mouse epidermis is counteracted by topical retinoids [8]. It has been shown that the epidermal hyperplasia induced by topical retinoids was linked to a RA receptor (RAR)-dependent heparin-binding epidermal growth factor (HB-EGF) paracrine loop [13]. Heparin-binding epidermal growth factor (HB-EGF) activation of keratinocyte erbB receptors has been proposed to mediate retinoid-induced epidermal hyperplasia. We have recently shown that intermediate size HA fragments (HAFi) reverse skin atrophy by a CD44-dependent mechanism
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