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.
Highlights
Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing
Our observations provide a novel CD44-dependent mechanism for HA oligosaccharideinduced keratinocyte proliferation and suggest that topical intermediate-size small-size HAF (HAFs) (HAFi) application may provide an attractive therapeutic option in human skin atrophy
Our observations indicate that HAF of 50,000–400,000 Da, defined as intermediate-size HAF (HAFi), induce keratinocyte proliferation and skin hyperplasia by a CD44-dependent mechanism that requires proteolytic activation of HB-epidermal-like growth factor (EGF) and engagement of erbB1
Summary
Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. The cells in the epidermis are mainly keratinocytes These specialized skin cells are continually produced at the base of the epidermis. They move toward the skin’s surface where they are shed. It is about ten times thicker than the epidermis and contains the blood vessels that feed the skin, nerves, sebaceous glands, and hair follicles. The dermis contains collagen fibers that support the skin and elastin fibers that provide flexibility. The dermis thins, and loss of collagen and elastin fibers means that the skin becomes less elastic. The gradual loss of epidermis and dermis—skin atrophy—is clinically important because aging skin is more fragile and heals slower than young skin and is prone to ulceration
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