synergistic effect of hyaluronate fragments in retinaldehyde-induced skin hyperplasia which is a cd44-dependent phenomenon协同效应的玻璃碎片retinaldehyde-induced皮肤增生cd44-dependent现象.pdfVIP

Synergistic Effect of Hyaluronate Fragments in Retinaldehyde-Induced Skin Hyperplasia Which Is a Cd44-Dependent Phenomenon 1 1 1 1 1 1 Laurent Barnes , Christian Tran , Olivier Sorg , Raymonde Hotz , Denise Grand , Pierre Carraux , Liliane 1 2 1 ¨ 1 Didierjean , Ivan Stamenkovic , Jean-Hilaire Saurat , Gurkan Kaya * 1 Department of Dermatology, University of Geneva, Geneva, Switzerland, 2 Institute of Pathology, University of Lausanne, Lausanne, Switzerland Abstract Background: CD44 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 Findings: Treatment 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 CD442/ 2 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