Hyaluronate Fragments Reverse Skin Atrophy by a CD44-Dependent Mechanism

Abstract

BackgroundSkin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeutic options at present.Methods and FindingsAtrophic skin displays a decreased hyaluronate (HA) content and expression of the major cell-surface hyaluronate receptor, CD44. In an effort to develop a therapeutic strategy for skin atrophy, we addressed the effect of topical administration of defined-size HA fragments (HAF) on skin trophicity. Treatment of primary keratinocyte cultures with intermediate-size HAF (HAFi; 50,000–400,000 Da) but not with small-size HAF (HAFs; <50,000 Da) or large-size HAF (HAFl; >400,000 Da) induced wild-type (wt) but not CD44-deficient (CD44−/−) keratinocyte proliferation. Topical application of HAFi caused marked epidermal hyperplasia in wt but not in CD44−/− mice, and significant skin thickening in patients with age- or corticosteroid-related skin atrophy. The effect of HAFi on keratinocyte proliferation was abrogated by antibodies against heparin-binding epidermal growth factor (HB-EGF) and its receptor, erbB1, which form a complex with a particular isoform of CD44 (CD44v3), and by tissue inhibitor of metalloproteinase-3 (TIMP-3).ConclusionsOur observations provide a novel CD44-dependent mechanism for HA oligosaccharide-induced keratinocyte proliferation and suggest that topical HAFi application may provide an attractive therapeutic option in human skin atrophy.

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

“…Similar to the bone and muscle atrophy, also the skin is atrophic in mutant mice and intrinsically aged mice. A comparable skin atrophy in intrinsically aged mice and humans has repeatedly been reported (Oikarinen, 1994;Scharffetter-Kochanek et al, 1997;Kaya et al, 2006). As expected, dermal fibroblasts from mutant mice revealed an increase in superoxide anion concentration and a decrease in hydrogen peroxide concentration in the mitochondria.…”

Isolation of all CD44 transcripts in human epidermis and regulation of their expression by various agents

“…In this study, we have selected epidermis, specifically, for several reasons: (i) CD44 is the cell surface receptor for HA and HA is the major component of the epidermal intercellular matrix involved in the nutrition of this non-vascularized tissue, in regulation of the gradients of ions and growth factors, and in promotion of keratinocyte responses to wound healing stimuli [40].…”

A Placebo-Controlled Study Demonstrates the Long-Lasting Anti-Aging Benefits of a Cream Containing Retinol, DihydroxyMethylChromone (DMC) and Hyaluronic Acid

“…Several publications demonstrate that fragments of HA could also play a role in the epidermal physiology, by binding to specific receptors such as CD44, expressed on keratinocyte, and that topical use of HA fragments of around 50 -400 kd could reverse epidermal atrophy in mice [35]. Also, it has been demonstrated recently that low molecular weight HA fragments of 50 kd could be delivered in reconstructed epidermis, and induced expression of different genes implicated in the terminal differentiation of keratinocytes, such as claudin and occludin genes [36].…”