Abstract
Skin Aging manifests primarily with wrinkles, dyspigmentations, texture changes, and loss of elasticity. During the skin aging process, there is a loss of moisture and elasticity in skin resulting in loss of firmness finally leading to skin sagging. The key molecule involved in skin moisture is hyaluronic acid (HA), which has a significant water-binding capacity. HA levels in skin decline with age resulting in decrease in skin moisture, which may contribute to loss of firmness. Clinical trials have shown that topically applied ROL effectively reduces wrinkles and helps retain youthful appearance. In the current study, ROL was shown to induce HA production and stimulates the gene expression of all three forms of hyaluronic acid synthases (HAS) in normal human epidermal keratinocytes monolayer cultures. Moreover, in human skin equivalent tissues and in human skin explants, topical treatment of tissues with a stabilized-ROL formulation significantly induced the gene expression of HAS mRNA concomitant with an increased HA production. Finally, in a vehicle-controlled human clinical study, histochemical analysis confirmed increased HA accumulation in the epidermis in ROL-treated human skin as compared to vehicle. These results show that ROL increases skin expression of HA, a significant contributing factor responsible for wrinkle formation and skin moisture, which decrease during aging. Taken together with the activity to increase collagen, elastin, and cell proliferation, these studies establish that retinol provides multi-functional activity for photodamaged skin.
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References
Baumann L (2007) Skin ageing and its treatment. J Pathol 211:241–251
Bellemère G, Stetten OV, Oddos T (2008) Retinoic acid increases aquaporin 3 expression in normal human skin. J Invest Dermatol 128:542–548
Jenkins G (2002) Molecular mechanisms of skin ageing. Mech Ageing Dev 123:801–810
Naylor EC, Watson RE, Sherratt MJ (2011) Molecular aspects of skin ageing. Maturitas 69:249–256
Rossetti D, Kielmanowicz MG, Vigodman S et al (2011) A novel anti-ageing mechanism for retinol: induction of dermal elastin synthesis and elastin fiber formation. Int J Cosmet Sci 33:62–69
Dicker KT, Gurski LA, Pradhan-Bhatt S et al (2014) Hyaluronan: a simple polysaccharide with diverse biological functions. Acta Biomater 10:1558–1570
Fakhari A, Berkland C (2013) Applications and emerging trends of hyaluronic acid in tissue engineering, as a dermal filler and in osteoarthritis treatment. Acta Biomater 9:7081–7092
Robert L, Robert AM, Renard G (2010) Biological effects of hyaluronan in connective tissues, eye, skin, venous wall. Role in aging. Pathol Biol 58:187–198
Stern R, Maibach HI (2008) Hyaluronan in skin: aspects of aging and its pharmacologic modulation. Clin Dermatol 26:106–122
Stern R, Kogan G, Jedrzejas MJ, Soltes L (2007) The many ways to cleave hyaluronic acid. Biotechnol Adv 25:537–557
Itano N, Kimata K (2002) Mammalian Hyaluronan Synthases. IUBMB Life 54:195–199
Lee A, Grummer SE, Kriegel D, Marmur E (2010) Hyaluronidase. Dermatol Surg 36:1071–1077
Volpi N, Schiller J, Stern R, Soltes L (2009) Role, metabolism, chemical modifications and application of hyaluronic acid. Curr Med Chem 16:1718–1745
Longas MO, Russell CS, He XY (1987) Evidence for structural changes in dermatan sulfate and hyaluronic acid with aging. Carbohydr Res 159:127–136
Ghersetich I, Lotti T, Campanile G et al (1994) Hyaluronic acid in cutaneous intrinsic aging. Int J Dermatol 33:119–122
Meyer LJM, Stern R (1994) Age-dependent changes of hyaluronan in human skin. J Invest Dermatol 102:385–389
Varani J, Warner RL, Gharaee-Kermani M et al (2000) Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol 114:480–486
Ong DE (1994) Cellular transport and metabolism of vitamin A: Roles of the cellular retinoid-binding proteins. Nutr Rev 52:24–31
Napoli JL, Boerman MHEM, Chai X et al (1995) Enzymes and binding proteins affecting retinoic acid concentrations. J Steroid Biochem Mol Biol 53:497–502
Kang S, Duell EA, Fisher GJ et al (1995) Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding protein characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol 105:549–556
Elder JT, Kaplan A, Cromie MA et al (1996) Retinoid induction of CRABP-II mRNA in dermal fibroblasts: use as a retinoid bioassay. J Invest Dermatol 106:517–521
Yoshimura K, Uchida G, Okazaki M et al (2003) Differential expression of heparin-binding EGF-like growth factor (Hb-EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids. Exp Dermatol 12(Suppl. 2):28–34
Kim JE, Kim B, Kim H et al (2010) Retinyl retinoate induces hyaluronan production and less irritation than other retinoids. J Dermatol 37:448–454
Margelin D, Medaisko C, Lombard D et al (1996) Hyaluronic acid and dermatan sulfate are selectively stimulated by retinoic acid in irradiated and nonirradiated hairless mouse skin. J Invest Dermatol 106:505–509
Sayo T, Sugiyama Y, Inooue S (2013) Lutein, a nonprovitamin A, activates the retinoic acid receptor to induce HAS3-dependent hyaluronan synthesis in keratinocytes. Biosci Biotechnol Biochem 77:1282–1286
Tammi R, Ripellono JA, Margolis RU et al (1989) Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture. J Invest Dermatol 92:326–332
Kligman AM, Dogadkina D, Lavker RM (1993) Effects of topical tretinoin on non-sun exposed protected skin of the elderly. J Am Acad Dermatol 29:25–33
Kafi R, Kwak HS, Schumacher WE et al (2007) Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol 143:606–612
Yoshida K, Sekine T, Matsuzaki F et al (1999) Stability of vitamin A in oil-in-water-in-oil-type multiple emulsions. J Am Oil Chem Soc 76:1–6
Tucker-Samaras S, Zedayko T, Cole C et al (2009) A stabilized 0.1% retinol facial moisturizer improves the appearance of photodamaged skin in an eight-week, double-blind, vehicle-controlled study. J Drugs Dermatol 8:932–936
Randhawa M, Rossetti D, Leyden JJ et al (2015) One-year topical stabilized retinol treatment improves photodamaged skin in a double-blind, vehicle-controlled trial. J Drugs Dermatol 14:271–280
Bellemère G, Stamatas GN, Bruère V et al (2009) Antiaging action of Retinol: from molecular to clinical. Skin Parmacol Physiol 22:200–209
Recklies AD, White C, Melching L, Roughley PJ (2001) Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells. Biochem J 354:17–24
Sayo T, Sugiyama Y, Takahashi Y et al (2002) Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes. J Invest Dermatol 118:43–48
Sayo T, Sakai S, Inoue S (2004) Synergistic effect of N-acetylglucosamine and retinoids on hyaluronan production in human keratinocytes. Skin Pharmacol Physiol 17:77–83
Takahashi N, Takasu S (2011) A close relationship between type 1 diabetes and vitamin A-deficiency and matrix metalloproteinase and hyaluronidase activities in skin tissues. Exp Dermatol 20:899–904
Acknowledgements
We gratefully thank Dr. Yaping Hu for his contributions, and Anne-Sophie Brillouet and David Byren for providing the product formulations.
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This study was funded by Johnson & Johnson Consumer Inc.
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The authors were employees of Johnson & Johnson Consumer Inc. when these experiments were conducted.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 2013 Helsinki declaration and its later amendments or comparable ethical standards.
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Wen-Hwa Li and Heng-Kuan Wong equal contribution.
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Li, WH., Wong, HK., Serrano, J. et al. Topical stabilized retinol treatment induces the expression of HAS genes and HA production in human skin in vitro and in vivo. Arch Dermatol Res 309, 275–283 (2017). https://doi.org/10.1007/s00403-017-1723-6
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DOI: https://doi.org/10.1007/s00403-017-1723-6