SKINIPEDIA - Skin Diseases: Reverse Skin Atrophy
Kim Yancey, Academic Editor
Medical College of Wisconsin, United States of America
* To whom correspondence re: this article should be addressed. E-mail: gkaya@hcuge.ch
Background
Skin 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 Findings
Atrophic 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).
Conclusions
Our 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.
INTRODUCTION
Skin atrophy is a frequent and clinically relevant manifestation of aging, often complicated by ulceration and impaired wound healing. Experimental evidence suggests that defective function of the principal cell-surface hyaluronate (HA) receptor CD44, which is associated with impaired HA metabolism, may underlie the pathogenesis of this disorder. HA is the most abundant glycosaminoglycan in cutaneous tissues and is deposited in the extracellular matrix as a high-molecular-weight polymer. Cleavage of the HA polymer during tissue remodeling gives rise to lower-molecular-weight fragments that elicit a variety of CD44-mediated cellular responses, including proliferation, migration, and cytokine synthesis. Increasing evidence suggests that cellular responses elicited by HA depend on the size of the HA oligosaccharides as well as on the responding cell type. Thus, HA fragments (HAF), but not native HA polymer or HA disaccharides, could activate Ras and PKCζ in tumor cells in a CD44-dependent fashion; 35,000- to 280,000-Da HA preparations were shown to stimulate CD44-mediated chemokine gene expression in alveolar macrophages; HA oligosaccharides have been reported to induce a toll-like receptor–mediated response in endothelial cells; and only tetra- and hexasaccharide HA fragments have been observed to induce immunophenotypic maturation of human dendritic cells.
Cellular responses to HA are primarily mediated by CD44, the most broadly expressed cell-surface HA receptor whose function is regulated at transcriptional, translational, and post-translational levels. Expression levels, variant isoform selection, and glycosylation all play an important role in the ability of CD44 to bind HA [11,12]. Because of its polymeric structure, HA can crosslink several CD44 molecules on the surface of a cell, an effect that is believed to be essential in triggering proliferative, invasive, and promigratory signals [11]. HA-mediated CD44 clustering can have a variety of effects, depending, at least in part, on the CD44 isoform that is implicated in HA binding. Thus, in mouse mammary and uterine epithelia, HA can induce heparan sulfate–bearing variants of CD44 (CD44v3) to recruit a cell-surface complex that includes matrix metalloproteinase 7 (MMP-7), heparin-binding epidermal-like growth factor (HB-EGF) precursor HB-EGF (pro-HB-EGF), and erbB4 [13]. MMP-mediated HB-EGF activation within this complex promotes epithelial cell survival in the lactating mammary gland and postpartum uterus [13]. CD44v3 isoforms are expressed in skin keratinocytes, where HA has been shown to regulate keratinocyte proliferation [3]. CD44 in turn appears to play an important role in maintaining HA homeostasis in skin [3], and its levels appear to correlate with skin trophicity. Thus, decreased epidermal CD44 expression is associated with the pathogenesis of an atrophic skin disorder known as lichen sclerosus et atrophicus [14]. Conversely, epidermal hyperplasia induced by topical administration of retinoids in mouse skin is accompanied by increased CD44 and HA synthase (HAS) expression with a concomitant increase in HA deposition [15]. To elucidate the mechanism whereby HA might induce keratinocyte proliferation, and to determine the response of the epidermis to its application in vivo, we examined the effect of HAF of varying size on in vitro–cultured mouse keratinocyte growth, and skin trophicity of DBA/1 wild-type (wt) and CD44−/− mice SKH1 hairless mice, as well as normal and atrophic human skin. 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-EGF and engagement of erbB1.
Reverse Skin Atrophy Article Part II
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