Ageing Skin: Oestrogen Receptor Agonists Offer an Approach To
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DOI:10.1111/j.1600-0625.2011.01362.x www.blackwellpublishing.com/EXD Viewpoint Ageing skin: oestrogen receptor b agonists offer an approach to change the outcome Richard L. Jackson, Jeffrey S. Greiwe and Richard J. Schwen Ausio Pharmaceuticals, LLC, Cincinnati, OH, USA Correspondence: Richard L. Jackson, PhD, Ausio Pharmaceuticals, LLC, 1776 Mentor Ave. Cincinnati, OH 45212, USA, Tel.: 513-731-0333, Fax: 513-731-0444, e-mail: [email protected] Abstract: Oestrogen (17b estradiol) and the dietary antioxidants regulates keratinocyte cell proliferation and migration. Based on resveratrol, genistein and S-equol, an isoflavone produced from their selectivity, ERb agents provide a treatment option for ageing the gut biotransformation of soy daidzein, are effective agents to skin without the potential safety issues associated with oestrogen reduce ageing in skin. It is widely held that these antioxidants therapy. scavenge free radicals to prevent skin damage. However, the Key words: AP-1 – oestrogen receptor b – photoaging – resveratrol – evidence to date suggests that the primary mechanism of action of S-equol these antioxidants is to activate oestrogen receptor b (ERb), which in turn enhances the expression of antioxidant enzymes and Accepted for publication 8 August 2011 inhibits the expression of snail, a transcription factor that Ageing skin: scope of the problem tion (EMT), promoting keratinocyte proliferation (7). Cysteine- ‘Old age isn’t so bad when you consider the alternative’ (Maurice rich protein-61 (CYR61) is another AP-1-activated protein that is Chevalier-New York Times, 9 October 1960). Although ageing elevated in the dermis of photoaged skin. Quan et al. (8) have skin has minimal effects on long-term health, more than $50 bil- shown that UV irradiation of human skin causes a sixfold increase lion a year is spent on skin products, which claim to prevent or in CYR61 mRNA and a fivefold decrease in collagen 1 protein. reverse the ageing process. Although the skin is the largest organ Oestrogen protects skin from ageing in the body, it is one of the least studied and we know very little Although there is much to learn about the molecular pathways about the changes that occur with ageing. It is known that oestro- that affect skin, it is known that chronological ageing is associated gen plays a key role in ageing skin. In this viewpoint, we present with decreased skin thickness and increased elasticity and dryness the evidence for a selective oestrogen receptor b (ERb) agonist as in both men and women. Clinical studies have shown that oestro- an agent to prevent the ageing process. gen treatment improves skin quality in women and men Reactive oxygen activates transcription factors (Table 1). Rittie´ et al. (12) evaluated the effects of topical oestro- AP-1 and snail in skin gen on procollagen expression in elderly (mean age 75 years) men Fine wrinkles, dry skin, hair loss and hyperpigmented spots are and women. Volunteers were treated with 17b estradiol on sun- early indications of skin ageing. The accumulation of collagen protected hip or on photodamaged skin obtained from the fore- breakdown products is a hallmark of ageing skin and results in a arm or face. For the sun-protected hip, oestrogen treatment decrease in mechanical tension that leads to wrinkles (1). Age- increased the amount of types 1 and 3 procollagen mRNA and related differences in the amount and structure of proteoglycans protein in women; oestrogen also increased procollagen expression that bind to collagen also determine the mechanical properties of in men, though to a lesser extent than in women. Oestrogen treat- skin (2). There are multiple pathways (3) that can contribute to ment had no effect on procollagen expression in the photodam- ageing skin, presenting a challenge for treatment. Both natural aged skin in the forearm or face in men or women. The lack of skin ageing and photoageing owing to exposure to the sun gener- effect of oestrogen on photoaged skin could be related to the older ate the superoxide radical (O2·) that activates the transcription age of the subjects, the short time of treatment or to irreversible factor AP-1 (Fig. 1). This transcription factor consists of heterodi- genetic changes that occurred during the ageing process. mers of c-Jun and c-Fos. Phosphorylation of c-Jun by mitogen- An interesting question raised by the Rittie´ et al. (12) study is activated protein kinases (MAP kinases) leads to increased AP-1 whether treatment at an earlier age would have made a difference activity (4); retinoids, a mainstay for the treatment of photoage- in the response to oestrogen on the photoaged skin of the ing, inhibit the activation of c-Jun. Activated AP-1 binds to the 75-year-old subjects. In this regard, Wolff et al. (10) reported that promoter region of the procollagen gene to inhibit its transcrip- postmenopausal women who had used hormone therapy (HT) tion, thus reducing the amount of collagen in skin. AP-1 also acti- continuously within 1 year of their last menstrual period had sig- vates the matrix metalloproteinase genes MMP-1 (collagenase), nificantly lower wrinkle scores and skin rigidity, as measured by MMP-3 (stromelysin) and MMP-9 (gelatinase), enzymes that the durometer, than women who had never used HT. In another degrade collagen (5). Another protein that is induced with UV study (9), also with younger subjects, postmenopausal women irradiation through AP-1 is snail (6), a transcription factor that aged 46–58 already using oral or transdermal oestrogen for at least plays an important role in the epithelial-to-mesenchymal transi- 1 year were then treated with topical 0.01% micronized 17b estra- ª 2011 John Wiley & Sons A/S, Experimental Dermatology 1 Jackson et al. UV Light UV Light nist for both ERa and ERb, reversed the inhibition of MMP-1 expression by WAY-200070. Furthermore, WAY-200070 had no SOD Catalase Keap 1/Nrf2 Mitochondrial O · H O O + H O metabolism 2 2 2 2 2 effect on the expression of MMP-13 (the mouse equivalent to Nrf2 Keap 1 human MMP-1) in the ERb knockout mouse, indicating that ERb ↑ AP - 1 ↑Antioxidant Nrf2 ERβ is required for MMP-1 expression. To show that ERb is protective ↑ Snail enzymes Promoter region of ↑ MMPs against UV-induced damage, Chang et al. (18) exposed mouse antioxidant enzymes ARE ERE skin to UV irradiation three times a week for 6 weeks. Impor- Figure 1. Activation of antioxidant enzymes is a key defense mechanism to tantly, ERB-041 was applied to the skin after irradiation, ruling prevent oxidative damage in skin. Superoxide radical (O2·) is produced by exposure out a free radical-scavenging mechanism. ERB-041 significantly to UV light and by cellular mitochondrial metabolism. O2· causes upregulation of reduced wrinkle formation at all concentrations tested, providing the transcription factors AP-1 and snail that leads to a decrease in collagen synthesis and increased collagen degradation by metalloproteinases (MMPs). direct evidence for the role of ERb in protecting skin from photo- Superoxide dismutase breaks down O2· into hydrogen peroxide (H2O2) that is damage. further metabolized to oxygen and water. The amount of antioxidant enzymes is upregulated by NF-E2-related factor (Nrf2) binding to an antioxidant response The isoflavones genistein and S-equol represent another class of element and oestrogen receptor b binding to an oestrogen response element ERb-selective agonists (21) that have positive effects on skin. An within the promoter region of the DNA for the antioxidant enzyme. isoflavone extract from soy cake and genistein, the major isoflav- one present in soy, reduced UV-induced cell death in the human diol on the face once a day for 16 weeks. Epidermal thickness, keratinocyte cell line HaCaT and attenuated the level of erythema dermal thickness and the amount of total collagen were signifi- when applied topically to mouse skin prior to irradiation (22). In cantly higher after the topical treatment. These results demonstrate humans, oral daily intake of 40 mg of soy isoflavone aglycones that HT provided some benefit to skin and that it could be further improved skin elasticity of middle age (late 30s and early 40s) Jap- improved later in life by topical application of oestrogen. anese women (23). In another study with Caucasian women (24), Agents that activate ERb prevent photoageing aged 45–65, consumption of a soy-based drink significantly Our understanding of the mechanism(s) of oestrogen’s action in reduced wrinkle depth in the crow’s foot area of the eye as com- skin has continued to evolve since this topic was reviewed in pared to the control group; the test group had increased synthesis 2002 (13). Oestrogen’s action occurs through two oestrogen of type 1 procollagen. S-equol is not present in soy but is pro- receptors, ERa and ERb, that are related but distinct nuclear hor- duced in some individuals, particularly Asians, by the gut bio- mone receptors. The selectivity of an oestrogen receptor agonist transformation of soy daidzein (25). Being an ‘equol producer’ for ERa or ERb is determined by its relative binding affinity, dif- has many health benefits, including fewer menopausal symptoms ferences in transcriptional activity and the tissue distribution of and increased bone mineral density (26). Whether improved skin the receptors (14). Keratinocytes express mainly ERb with little or in subjects consuming soy isoflavones is attributable to S-equol no ERa (15,16). In contrast, dermal fibroblasts express both ERa needs to be determined using pure S-equol. However, animal and ERb (17). Several lines of evidence indicate that ERb is a key studies show that topical racemic equol is photo- and photoim- target for prevention of photoageing (18), wound healing (19) muno-protective after UV irradiation (27–31).