Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism
| Autor: | Jean-Hilaire Saurat, Olivier Sorg, Pierre Carraux, Christian Tran, Liliane Didierjean, Raymonde Hotz, Gürkan Kaya, Ivan Stamenkovic, Denise Grand |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Keratinocytes
Male Pathology Geriatric Medicine Oligosaccharides lcsh:Medicine Human skin Filaggrin Proteins Biochemistry Mice 030207 dermatology & venereal diseases chemistry.chemical_compound 0302 clinical medicine Intermediate Filament Proteins Epidermal growth factor Hyaluronic acid Hyaluronic Acid Receptor Cells Cultured Skin Mice Knockout 0303 health sciences biology integumentary system General Medicine 3. Good health ErbB Receptors Platelet Endothelial Cell Adhesion Molecule-1 Hyaluronan Receptors medicine.anatomical_structure Drugs and adverse drug reactions Female Keratinocyte Research Article Adult Immunology and allergy medicine.medical_specialty Blotting Western Immunology Dermatology Skin Diseases 03 medical and health sciences Atrophy Dermis medicine Animals Humans Immunoprecipitation Vimentin Cell Proliferation 030304 developmental biology Epidermal Growth Factor CD44 lcsh:R Antigens CD31 Antigens CD44 Membrane Proteins Receptor Epidermal Growth Factor medicine.disease chemistry Geriatrics biology.protein |
| Zdroj: | PLoS Medicine, Vol 3, Iss 12, p e493 (2006) PLoS Medicine PLoS Medicine, vol. 3, no. 12, pp. e493 |
| ISSN: | 1549-1676 1549-1277 |
| Popis: | 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; 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. Mouse and human data suggest that topical application of intermediate-size hyaluronate fragments holds therapeutic potential for skin atrophy. Editors' Summary Background. Time wreaks many changes in the human body but the skin is where one of the first visible signs of aging—wrinkles—occurs. The skin consists of three main layers. The outermost layer is the epidermis. It is the thickness of a sheet of paper and forms a barrier that prevents the body losing water or infectious agents entering it. The cells in the epidermis are mainly keratinocytes. These specialized skin cells are continually produced at the base of the epidermis. From there, they move toward the skin's surface where they are shed. The middle layer is the dermis. 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 final, subcutaneous layer contains sweat glands, some hair follicles, blood vessels and fat. The dermis contains collagen fibers that support the skin and elastin fibers that provide flexibility. Human skin begins to age in early adulthood. By the time a person is 80 years old, their epidermis may be half its original thickness because of decreased keratinocyte proliferation. The dermis also 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 also prone to ulceration. Why Was This Study Done? No one knows why skin atrophy occurs, but it is becoming more common as people live longer, and there is no effective treatment for it. One characteristic of atrophic skin is that, compared to normal skin, it contains less hyaluronate (also called hyaluronan and hyaluronic acid)—a large carbohydrate component of the extracellular matrix, the material that surrounds cells. It also contains less CD44, a cell-surface protein that interacts with hyaluronate. This interaction can stimulate cell proliferation and migration. Given these observations, in this study the researchers have investigated whether treating atrophic skin with fragments of hyaluronate might counteract atrophy. What Did the Researchers Do and Find? The researchers isolated keratinocytes from normal mice and from CD44-deficient mice (CD44−/− mice) and treated them with different sized fragments of hyaluronate. Intermediate sized hyaluronate fragments (so-called HAFi) but not large or small fragments increased the proliferation of normal keratinocytes but not CD44−/− keratinocytes. This suggests that proliferation in response to HAFi is CD44-dependent. Similarly, a cream of HAFi applied to the backs of normal mice caused thickening of the epidermal layer but had no effect on CD44−/− mice. Finally, topical application of HAFi for one month caused skin thickening and clinical improvement in six people with skin atrophy but had no effect on normal human skin. The collagen, elastic fiber, and blood vessel content of the dermis also increased in treated patients. By using antibodies to block the function of various proteins, the researchers also discovered that heparin-binding epidermal growth factor (HB-EGF, a protein that stimulates keratinocyte proliferation), erbB1 (a cell-surface protein that binds HB-EGF), and matrix metalloproteinases (proteins that activate HB-EGF) are all required for the stimulation of keratinocyte proliferation by HAFi. What Do These Findings Mean? Taken together, these results provide the first indication that application of HAFi to atrophic skin might be useful therapeutically. The absence of any effect on normal human skin is reassuring but puzzling given the thickening seen in normal mouse skin, so this finding needs confirmation before hyaluronate fragments are used clinically. Longer trials in more people are also needed to characterize the clinical effects fully. Finally, the mechanism by which hyaluronate fragments have their effect needs to be studied in more depth. Such studies might reveal other potential therapeutic options for the treatment of skin atrophy. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030493. MedlinePlus encyclopedia entry on aging changes in skin US National Institute on Aging, patient information on skin care and aging American Academy of Dermatology, patient information on aging skin Information on CD44, the hyaluronan receptor, provided by Glycoforum a source of information on glycobiology Wikpedia pages on skin and on hyaluronan (note that Wikipedia is a free online encyclopedia that anyone can edit) |
| Databáze: | OpenAIRE |
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