Synergistic Effect of Hyaluronate Fragments in Retinaldehyde-Induced Skin Hyperplasia Which Is a Cd44-Dependent Phenomenon

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.

Lrig1 and CD44v3 Expression in the Human Folliculosebaceous Unit

“…We next studied the expression of EGFR and CD44v3 in these clusters, since CD44v3 has been shown to modulate EGFR signaling [6,7,8]. Two human skin serial sections from the scalp and from the retroauricular area were stained with antibodies directed against the human form of Lrig1 [1,9,10], EGFR (Cell Signaling, #4267, Danvers, Mass., USA) and CD44v3 (BMS144, Bender MedSystems, Vienna, Austria).…”

Hyaluronan Inside and Outside of Skin

“…But the proper form of Vitamin A for human oral consumption and for maximal effect has still not been established. Synergistic effects of hyaluronate fragments occur in retinaldehyde-induced skin hyperplasia, which appears to be a CD44-dependent phenomenon [ 6 ] .…”

575 Senescent atrophic epidermis retains Lrig1+ stem cells and loses Wnt signaling, a phenotype shared with 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].…”