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.

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Background: UV irradiation can deplete epidermal vitamin A, thus the hypothesis that UV-induced depletion of vitamin A in sun-exposed skin is involved in the pathogenesis of skin cancers and skin ageing. Objectives: In this study we addressed two questions: (1) Are retinol (ROL) and retinyl esters (RE) – the two predominant forms of vitamin A – equally sensitive to the action of UVB, and (2) could the depletion be prevented by anti-oxidants? Methods: Hairless mice were irradiated with a single UVB dose, corresponding to the maximum of ROL and RE absorption. Retinoid content, enzyme activities catalysing the esterification of ROL (ARAT and LRAT) and the hydrolysis of RE (REH), as well as retinol-binding protein (CRBP-1) expression were determined in the epidermis. Results: A single UVB dose induced a rapid, dose-dependent decrease in both ROL and RE in the epidermis of hairless mice, with partial replenishment after 24 h. The dose-response curve for ROL showed a high sensitivity to UV at doses not exceeding 200 mJ/cm², followed by a plateau, whereas RE underwent a continuous dose-dependent decrease at UVB doses up to 1 J/cm². A topical anti-oxidant mixture containing 0.5% ascorbate, 0.25% tocopherol and 0.25% melatonin failed to protect epidermal RE from UVB-induced depletion, whereas it did prevent ROL depletion. ARAT and REH, as well as CRBP-1, were not affected by UVB in these conditions. Conclusion: Vitamin A storage in the epidermis comprises two forms, ROL and RE, that do not show similar sensitivity to acute UVB exposure. ROL stores comprise a UVB-resistant (possibly by CRBP) portion and a UVB-sensitive portion that can be protected by anti-oxidants. RE stores do not show such a pattern.

Retinaldehyde, a natural metabolite of beta-carotene and retinol, has been proposed recently for topical use in humans. Because retinaldehyde does not bind to retinoid nuclear receptors, its biologic activity should result from enzymatic transformation by epidermal keratinocytes into ligands for these receptors, such as all-trans retinoic acid and 9-cis-retinoic acid. In this study, we analyzed by high performance liquid chromatography the type and amounts of tissue retinoids as well as several biologic activities resulting from topical application of either retinaldehyde or all-trans retinoic acid on mouse tail skin. Biologic activities of all-trans retinoic acid and retinaldehyde were qualitatively identical in metaplastic parameters (induction of orthokeratosis, reduction of keratin 65-kDa mRNA, increase in filaggrin and loricrin mRNAs) and hyperplastic parameters (increase in epidermal thickness, increase in bromodeoxyuridine (BrdU)-positive cells, increase in keratin 50-kDa mRNA, and reduction in keratin 70-kDa mRNA). Some quantitative differences, not all in favor of all-trans retinoic acid, were found in several indices. Cellular retinoic acid-binding protein II and cellular retinol-binding protein I mRNAs were increased by both topical retinaldehyde and all-trans retinoic acid. Whereas all-trans retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid were not detectable (limit 5 ng/g) in vehicle-treated skin, 0.05% retinaldehyde-treated skin contained 13 +/- 6.9 ng/g wet tissue of all-trans retinoic acid (mean +/- SD), 12.6 +/- 5.9 ng/g 13-cis-retinoic acid, and no 9-cis-retinoic acid. In contrast, 9-cis-retinoic acid was detectable in 0.05% of all-trans retinoic acid-treated skin, which also contained 25-fold more all-trans retinoic acid and 5-fold more 13-cis-retinoic acid than retinaldehyde-treated skin. Our results show that topical retinaldehyde is transformed in vivo into all-trans retinoic acid by mouse epidermis. The small amounts of ligand for retinoic acid nuclear receptors thus produced are sufficient to induce biologic effects similar to those resulting from the topical application of the ligand itself in much higher concentration.

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Retinyl esters, a storage form of vitamin A, concentrate in the epidermis, and absorb ultraviolet radiation with a maximum at 325 nm. We wondered whether these absorbing properties of retinyl esters might have a biologically relevant filter activity. We first used an in vitro model to assess the photoprotective properties of retinyl palmitate. We then applied topical retinyl palmitate on the back of hairless mice before exposing them to 1 J per cm2 ultraviolet B, and assayed the levels of thymine dimers produced in epidermal DNA 2 h following ultraviolet B exposure. Finally, we applied topical retinyl palmitate or a sunscreen on the buttocks of human volunteers before exposing them to four minimal erythema doses of ultraviolet B; we assayed the levels of thymine dimers produced 2 h following ultraviolet B exposure, and determined the intensity of erythema 24 h after ultraviolet B. In vitro, retinyl palmitate was shown to be as efficient as the commercial filter octylmethoxycinnamate in preventing ultraviolet-induced fluorescence or photobleaching of fluorescent markers. The formation of thymine dimers in mouse epidermis was significantly inhibited by topical retinyl palmitate. In human subjects, topical retinyl palmitate was as efficient as a sun protection factor 20 sunscreen in preventing sunburn erythema as well as the formation of thymine dimers. These results demonstrate that epidermal retinyl esters have a biologically relevant filter activity and suggest, besides their pleomorphic biologic actions, a new role for vitamin A that concentrates in the epidermis.

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