Nuclear Hormone Receptors in Human Skin

M. Schmuth; R. E. Watson; D. Deplewski; S. Dubrac; C. C. Zouboulis; C. E. Griffiths

doi:10.1055/s-2007-961808

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2007; 39(2): 96-105
DOI: 10.1055/s-2007-961808

Review

Nuclear Hormone Receptors in Human Skin

M. Schmuth¹ , R. E. Watson² , D. Deplewski³ , S. Dubrac¹ , C. C. Zouboulis⁴ ^, ⁵ , C. E. Griffiths²

¹Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria
²Dermatology Centre, Hope Hospital, University of Manchester, Salford, Manchester, UK
³Department of Pediatrics, Section of Pediatric Endocrinology, The University of Chicago Pritzker School of Medicine, Comer Children's Hospital, Chicago, IL, USA
⁴Departments of Dermatology and Immunology, Dessau Medical Center, Dessau, Germany
⁵Laboratory of Biogerontology, Dermato-Pharmacology and Dermato-Endocrinology, Institute of Clinical Pharmacology and Toxicology, Charité Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

Abstract

Nuclear hormone receptors are of critical importance for skin homeostasis where they modulate cellular metabolism, proliferation, differentiation, cell death, and inflammation. The cutaneous role of the glucocorticoid, androgen, and estrogen receptors was explored initially. In recent years, sequence homology comparisons have uncovered the complete superfamily of related receptors, many of which are also implicated in cutaneous homeostasis. A subgroup of these receptors acts in concert with the retinoid X receptor by heterodimerization and has been successfully targeted for dermatologic therapy; i.e., the retinoic acid receptor and the vitamin D receptor. Ongoing research is aimed at delineating the cutaneous effects of additional members of this subgroup including the peroxisome proliferator-activated receptors and the liver X receptors. The various receptors exert differential effects in skin and can be rationally chosen as drug targets for the treatment of cutaneous pathologies.

Keywords

epidermis - inflammation - psoriasis - skin cancer - transcription factor

Full Text

References

1 Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001; 294 1866-1870
2 Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med. 2005; 353 604-615
3 Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 2006; 126 789-799
4 Kariya Y, Moriya T, Suzuki T, Chiba M, Ishida K, Takeyama J, Endoh M, Watanabe M, Sasano H. Sex steroid hormone receptors in human skin appendage and its neoplasms. Endocr J. 2005; 52 317-325
5 Pelletier G, Ren L. Localization of sex steroid receptors in human skin. Histol Histopathol. 2004; 19 629-636
6 Kenouch S, Lombes M, Delahaye F, Eugene E, Bonvalet JP, Farman N. Human skin as target for aldosterone: coexpression of mineralocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab. 1994; 79 1334-1341
7 Grill HJ, Benes P, Manz B, Morsches B, Korting GW, Pollow K. Steroid hormone receptor analysis in human melanoma and non-malignant human skin. Br J Dermatol. 1982; 107 ((Suppl 23)) 64-65
8 Leiferman KM, Schroeter A, Kirschner MK, Spelsberg TC. Characterization of the glucocorticoid receptor in human skin. J Invest Dermatol. 1983; 81 355-361
9 Epstein Jr EH, Bonifas JM. Glucocorticoid receptors of normal human epidermis. J Invest Dermatol. 1982; 78 144-146
10 Ponec M, Kempenaar JA, De Kloet ER. Corticoids and cultured human epidermal keratinocytes: specific intracellular binding and clinical efficacy. J Invest Dermatol. 1981; 76 211-214
11 Hasselquist MB, Goldberg N, Schroeter A, Spelsberg TC. Isolation and characterization of the estrogen receptor in human skin. J Clin Endocrinol Metab. 1980; 50 76-82
12 Uzuka M, Nakajima K, Mori Y. Estrogen receptor in the mouse skin. Biochim Biophys Acta. 1978; 544 329-337
13 Kliewer SA, Lehmann JM, Willson TM. Orphan nuclear receptors: shifting endocrinology into reverse. Science. 1999; 284 757-760
14 Maglich JM, Sluder A, Guan X, Shi Y, McKee DD, Carrick K, Kamdar K, Willson TM, Moore JT. Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes. Genome Biol. 2001; 2 , RESEARCH 0029
15 Nuclear receptors nomenclature committee . A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999; 97 161-163
16 Beato M, Truss M, Chavez S. Control of transcription by steroid hormones. Ann N Y Acad Sci. 1996; 784 93-123
17 Napoli JL. Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1999; 1440 139-162
18 Icre G, Wahli W, Michalik L. Functions of the peroxisome proliferator-activated receptor (PPAR) alpha and beta in skin homeostasis, epithelial repair, and morphogenesis. J Investig Dermatol Symp Proc. 2006; 11 30-35
19 Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med. 1993; 329 530-535
20 Fanjul A, Dawson MI, Hobbs PD, Jong L, Cameron JF, Harlev E, Graupner G, Lu XP, Pfahl M. A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature. 1994; 372 107-111
21 Chen JY, Penco S, Ostrowski J, Balaguer P, Pons M, Starrett JE, Reczek P, Chambon P, Gronemeyer H. Rar-specific agonist/antagonists which dissociate transactivation and ap1 transrepression inhibit anchorage-independent cell proliferation. Embo J. 1995; 14 1187-1197
22 Fisher GJ, Talwar HS, Lin J, Voorhees JJ. Molecular mechanisms of photoaging in human skin in vivo and their prevention by all-trans retinoic acid. Photochem Photobiol. 1999; 69 154-157
23 Muramatsu M, Inoue S. Estrogen receptors: how do they control reproductive and nonreproductive functions?. Biochem Biophys Res Commun. 2000; 270 1-10
24 Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001; 104 719-730
25 Klotz DM, Hewitt SC, Ciana P, Raviscioni M, Lindzey JK, Foley J, Maggi A, DiAugustine RP, Korach KS. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (JGF-1)-induced uterine responses and in vivo evidence for JGF-1/estrogen receptor cross-talk. J Biol Chem. 2002; 277 8531-8537
26 Fillardo EJ. Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30; a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem Mol Biol. 2002; 277 8531-8537
27 Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov. 2004; 3 950-964
28 Kenouch S, Alfaidy N, Bonvalet JP, Farman N. Expression of 11 beta-OHSD along the nephron of mammals and humans. Steroids. 1994; 59 100-104
29 Im S, Lee ES, Kim W, Song J, Kim J, Lee M, Kang WH. Expression of progesterone receptor in human keratinocytes. J Korean Med Sci. 2000; 15 647-654
30 Jemec GBE, Wojnarowska F. The distribution of P29 protein in normal human skin. Br J Dermatol. 1987; 117 217-224
31 Feingold KR, Elias PM. Endocrine-skin interactions. Cutaneous manifestations of pituitary disease, thyroid disease, calcium disorders, and diabetes. J Am Acad Dermatol. 1987; 17 921-940
32 Hamilton J. Male hormone stimulation is prerequisite and an incitant in common baldness. Am J Anat. 1942; 71 451
33 Bonne C, Saurat JH, Chivot M, Lehuchet D, Raynaud JP. Androgen receptor in human skin. Br J Dermatol. 1977; 97 501-503
34 Feingold KR, Elias PM. Endocrine-skin interactions. Cutaneous manifestations of adrenal disease, pheochromocytomas, carcinoid syndrome, sex hormone excess and deficiency, polyglandular autoimmune syndromes, multiple endocrine neoplasia syndromes, and other miscellaneous disorders. J Am Acad Dermatol. 1988; 19 1-20
35 Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998; 20 284-287
36 Schmuth M, Elias PM, Feingold KR. Beyond glucocorticoids, retinoids and vitamin D-the evolution of nuclear hormone type transcription factor targeting in the skin. J Dtsch Dermatol Ges. 2003; 1 352-362
37 Di-Poi N, Michalik L, Desvergne B, Wahli W. Functions of peroxisome proliferator-activated receptors (PPAR) in skin homeostasis. Lipids. 2004; 39 1093-1099
38 Michalik L, Wahli W. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Invest. 2006; 116 598-606
39 Luger T, Loske KD, Elsner P, Kapp A, Kerscher M, Korting HC, Krutmann J, Niedner R, Rocken M, Ruzicka T, Schwarz T. topical skin therapy with glucocorticoids-therapeutic index]. J Dtsch Dermatol Ges. 2004; 2 629-634
40 Ortonne JP. Clinical potential of topical corticosteroids. Drugs. 1988; 36 ((Suppl 5)) 38-42
41 Stuttgen G. Historical perspectives of tretinoin. J Am Acad Dermatol. 1986; 15 735-740
42 van de Kerkhof PC. Biological activity of vitamin D analogues in the skin, with special reference to antipsoriatic mechanisms. Br J Dermatol. 1995; 132 675-682
43 Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs. 1997; 53 358-388
44 Pillai S, Bikle DD. Epidermal vitamin D metabolism, function, and regulation. Adv Lipid Res. 1991; 24 321-341
45 von Brenken S, Jensen JM, Fartasch M, Proksch E. Topical vitamin D3 derivatives impair the epidermal permeability barrier in normal mouse skin. Dermatology. 1997; 194 151-156
46 Fisher GJ, Voorhees JJ. Molecular mechanisms of retinoid actions in skin. Faseb J. 1996; 10 1002-1013
47 Fisher C, Blumenberg M, Tomic-Canic M. Retinoid receptors and keratinocytes. Crit Rev Oral Biol Med. 1995; 6 284-301
48 Gerritsen MJ, Boezeman JB, van Vlijmen-Willems IM, Van de Kerkhof PC. The effect of tacalcitol (1,24 (OH)2D3) on cutaneous inflammation, epidermal proliferation and keratinization in psoriasis: a placebo-controlled, double-blind study. Br J Dermatol. 1994; 131 57-63
49 Elias PM, Fritsch PO, Lampe M, Williams ML, Brown BE, Nemanic M, Grayson S. Retinoid effects on epidermal structure, differentiation, and permeability. Lab Invest. 1981; 44 531-540
50 van de Kerkhof PC, Kleinpenning MM, de Jong EM, Gerritsen MJ, van Dooren-Greebe RJ, Alkemade HA. Current and future treatment options for acne. J Dermatolog Treat. 2006; 17 198-204
51 Kang S, Duell EA, Kim KJ, Voorhees JJ. Liarozole inhibits human epidermal retinoic acid 4-hydroxylase activity and differentially augments human skin responses to retinoic acid and retinol in vivo. J Invest Dermatol. 1996; 107 183-187
52 Kang S, Li XY, Duell EA, Voorhees JJ. The X retinoid receptor agonist 9-cis-retinoic acid and the 24-hydroxylase inhibitor ketoconazole increase activity of 1,25-dihydroxyvitamin d3 in human skin in vivo. J Invest Dermatol. 1997; 108 513-518
53 Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, Crowley C, Yocum RC. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001; 19 2456-2471
54 Apisarnthanarax N, Duvic M. Therapy options in cutaneous T-cell lymphoma. Expert Rev Anticancer Ther. 2001; 1 403-420
55 Zhang C, Hazarika P, Ni X, Weidner DA, Duvic M. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res. 2002; 8 1234-1240
56 Kempf W, Kettelhack N, Duvic M, Burg G. Topical and sytemic retinoid therapy for cutaneous lymphoma. Hematol Oncol Clin North Am. 2003; 17 1405-1419
57 Miles SA, Dezube BJ, Lee JY, Krown SE, Fletcher MA, Saville MW, Kaplan L, Groopman J, Scadden DT, Cooley T, Von Roenn J, Friedman-Kien A. Antitumor activity of oral 9-cis-retinoic acid in HIV-associated Kaposi's sarcoma. Aids. 2002; 16 421-429
58 Duvic M, Friedman-Kien AE, Looney DJ, Miles SA, Myskowski PL, Scadden DT, Von Roenn J, Galpin JE, Groopman J, Loewen G, Stevens V, Truglia JA, Yocum RC. Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials. Arch Dermatol. 2000; 136 1461-1469
59 Saiag P, Pavlovic M, Clerici T, Feauveau V, Nicolas JC, Emile D, Chastang C. Treatment of early AIDS-related Kaposi's sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Kaposi's Sarcoma ANRS study group. Agence Nationale de Recherches sur le SIDA. Aids. 1998; 12 2169-2176
60 Bodsworth NJ, Bloch M, Bower M, Donnell D, Yocum R. Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi's sarcoma. Am J Clin Dermatol. 2001; 2 77-87
61 Bhakoo HS, Milholland RJ, Lopez R, Karakousis C, Rosen F. High incidence and characterization of glucocorticoid receptors in human malignant melanoma. J Natl Cancer Inst. 1981; 66 21-25
62 Kokoschka EM, Spona J, Knobler R. Sex steroid hormone receptor analysis in malignant melanoma. Br J Dermatol. 1982; 107 ((Suppl 23)) 54-59
63 Rumke P, Persijn JP, Korsten CB. Oestrogen and androgen receptors in melanoma. Br J Cancer. 1980; 41 652-656
64 Spanjaard RA, Ikeda M, Lee PJ, Charpentier B, Chin WW, Eberlein TJ. Specific activation of retinoic acid receptors (RARs) and retinoid X receptors reveals a unique role for RARgamma in induction of differentiation and apoptosis of S91 melanoma cells. J Biol Chem. 1997; 272 18990-18999
65 Siegrist W, Hintermann E, Roggo CN, Apfel CM, Klaus M, Eberle AN. Melanoma cell growth inhibition and melanocortin receptor downregulation induced by selective and non-selective retinoids. Melanoma Res. 1998; 8 113-122
66 Boehm N, Samama B, Cribier B, Rochette-Egly C. Retinoic-acid receptor beta expression in melanocytes. Eur J Dermatol. 2004; 14 19-23
67 Evans SR, Houghton AM, Schumaker L, Brenner RV, Buras RR, Davoodi F, Nauta RJ, Shabahang M. Vitamin D receptor and growth inhibition by 1,25-dihydroxyvitamin D3 in human malignant melanoma cell lines. J Surg Res. 1996; 61 127-133
68 Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology. 1981; 108 1083-1086
69 Seifert M, Rech M, Meineke V, Tilgen W, Reichrath J. Differential biological effects of 1,25-dihydroxyvitamin D3 on melanoma cell lines in vitro. J Steroid Biochem Mol Biol. 2004; 89-90 375-379
70 Danielsson C, Torma H, Vahlquist A, Carlberg C. Positive and negative interaction of 1,25-dihydroxyvitamin D3 and the retinoid CD437 in the induction of human melanoma cell apoptosis. Int J Cancer. 1999; 81 467-470
71 Hutchinson PE, Osborne JE, Lear JT, Smith AG, Bowers PW, Morris PN, Jones PW, York C, Strange RC, Fryer AA. Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma. Clin Cancer Res. 2000; 6 498-504
72 Halsall JA, Osborne JE, Potter L, Pringle JH, Hutchinson PE. A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma. Br J Cancer. 2004; 91 765-770
73 Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin d3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci USA. 2006; 103 11736-11741
74 Mossner R, Schulz U, Kruger U, Middel P, Schinner S, Fuzesi L, Neumann C, Reich K. Agonists of peroxisome proliferator-activated receptor gamma inhibit cell growth in malignant melanoma. J Invest Dermatol. 2002; 119 576-582
75 Mossner R, Meyer P, Jankowski F, Konig IR, Kruger U, Kammerer S, Westphal G, Boettger MB, Berking C, Schmitt C, Brockmoller J, Ziegler A, Stapelmann H, Kaiser R, Volkenandt M, Reich K. Variations in the peroxisome proliferator-activated receptor-gamma gene and melanoma risk. Cancer Lett. 2007; 246 218-223
76 Stedman KE, Moore GE, Morgan RT. Estrogen receptor proteins in diverse human tumors. Arch Surg. 1980; 115 244-248
77 Budunova IV, Carbajal S, Kang H, Viaje A, Slaga TJ. Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis. Mol Carcinog. 1997; 18 177-185
78 Lupulescu A. Hormonal regulation of epidermal tumor development. J Invest Dermatol. 1981; 77 186-195
79 Budunova IV, Kowalczyk D, Perez P, Yao YJ, Jorcano JL, Slaga TJ. Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis. Oncogene. 2003; 22 3279-3287
80 Stewart JW, Koehler K, Jackson W, Hawley J, Wang W, Au A, Myers R, Birt DF. Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition. Carcinogenesis. 2005; 26 1077-1084
81 Zackheim HS. Effect of castration on the induction of epidermal neoplasms in male mice by topical methylcholanthrene. J Invest Dermatol. 1970; 54 479-486
82 Finzi E, Blake MJ, Celano P, Skouge J, Diwan R. Cellular localization of retinoic acid receptor-gamma expression in normal and neoplastic skin. Am J Pathol. 1992; 140 1463-1471
83 Xu XC, Wong WY, Goldberg L, Baer SC, Wolf JE, Ramsdell WM, Alberts DS, Lippman SM, Lotan R. Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis. Cancer Res. 2001; 61 4306-4310
84 Chakravarti N, El-Naggar AK, Lotan R, Anderson J, Diwan AH, Saadati HG, Diba R, Prieto VG, Esmaeli B. Expression of retinoid receptors in sebaceous cell carcinoma. J Cutan Pathol. 2006; 33 10-17
85 Nijsten T, Geluyckens E, Colpaert C, Lambert J. Peroxisome proliferator-activated receptors in squamous cell carcinoma and its precursors. J Cutan Pathol. 2005; 32 340-347
86 Monzon RI, Fillmore C, Hudson LG. Functional consequences of reduced retinoic acid receptor gamma expression in a human squamous cell carcinoma line. Mol Pharmacol. 1997; 51 377-382
87 Jaeckel EC, Raja S, Tan J, Das SK, Dey SK, Girod DA, Tsue TT, Sanford TR. Correlation of expression of cyclooxygenase-2, vascular endothelial growth factor, and peroxisome proliferator-activated receptor delta with head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2001; 127 1253-1259
88 Kim DJ, Akiyama TE, Harman FS, Burns AM, Shan W, Ward JM, Kennett MJ, Gonzalez FJ, Peters JM. Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis. J Biol Chem. 2004; 279 23719-23727
89 Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer. 2004; 4 61-70
90 Thuillier P, Anchiraico GJ, Nickel KP, Maldve RE, Gimenez-Conti I, Muga SJ, Liu KL, Fischer SM, Belury MA. Activators of peroxisome proliferator-activated receptor-alpha partially inhibit mouse skin tumor promotion. Mol Carcinog. 2000; 29 134-142
91 Chen CF, Goyette P, Lohnes D. RARgamma acts as a tumor suppressor in mouse keratinocytes. Oncogene. 2004; 23 5350-5359
92 He G, Muga S, Thuillier P, Lubet RA, Fischer SM. The effect of PPARgamma ligands on UV- or chemically-induced carcinogenesis in mouse skin. Mol Carcinog. 2005; 43 198-206
93 Wolpowitz D, Gilchrest BA. The vitamin D questions: how much do you need and how should you get it?. J Am Acad Dermatol. 2006; 54 301-317
94 Izikson L, Bhan A, Zembowicz A. Androgen receptor expression helps to differentiate basal cell carcinoma from benign trichoblastic tumors. Am J Dermatopathol. 2005; 27 91-95
95 Hamilton KS, Johnson S, Smoller BR. The role of androgen receptors in the clinical course of nevus sebaceus of gadassohn. Mod Pathol. 2001; 14 539-542
96 Liang T, Hoyer S, Yu R, Soltani K, Lorincz AL, Hiipakka RA, Liao S. Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptor. J Invest Dermatol. 1993; 100 663-666
97 Lachgar S, Charveron M, Sarraute J, Mourard M, Gall Y, Bonafe JL. In vitro main pathways of steroid action in cultured hair follicle cells: vascular approach. J Investig Dermatol Symp Proc. 1999; 4 290-295
98 Fritsch M, Orfanos CE, Zouboulis CC. Sebocytes are the key regulators of androgen homeostasis in human skin. J Invest Dermatol. 2001; 116 793-800
99 Fimmel S, Saborowski A, Terouanne B, Sultan C, Zouboulis C. Inhibition of the androgen receptor by antisense oligunucleotides regulates the biological activity of androgens in SZ95 sebocytes. Horm Metab Res. , in press
100 Thornton MJ, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O'Driscoll J, Messenger AG. Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin. Exp Dermatol. 2003; 12 181-190
101 Makrantonaki E, Adjaye J, Herwig R, Brink TC, Groth D, Hultschig C, Lehrach H, Zouboulis CC. Age-specific hormonal decline is accompanied by transcriptional changes in human sebocytes in vitro. Aging Cell. 2006; 5 331-344
102 Reichrath J, Mittmann M, Kamradt J, Muller SM. Expression of retinoid- X receptors (-alpha, -beta, -gamma) and retinoic acid receptors (-alpha, -beta, -gamma) in normal human skin: an immunohistological evaluation. Histochem J. 1997; 29 127-133
103 Tsukada M, Schroder M, Roos TC, Chandraratna RA, Reichert U, Merk HF, Orfanos CE, Zouboulis CC. 13-cis Retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol. 2000; 115 321-327
104 Doran T, Lucas D, Levin A, Pacia E, Sturzenbecker L, Allenby G, Grippo J, Shapiro S. Biochemical and retinoid receptor activities in human sebaceous cells. In: Saurat J-H (ed) Retinoids: 10 years on. Basel: Karger 1991: 243-253
105 Reichrath J, Classen UG, Meineke V, DeLuca H, Tilgen W, Kerber A, Holick MF. Immunoreactivity of six monoclonal antibodies directed against 1,25-dihydroxyvitamin-D3 receptors in human skin. Histochem J. 2000; 32 625-629
106 Rosenfield RL, Deplewski D, Greene ME. Peroxisome proliferator-activated receptors and skin development. Horm Res. 2000; 54 269-274
107 Chen W, Yang CC, Sheu HM, Seltmann H, Zouboulis CC. Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes. J Invest Dermatol. 2003; 121 441-447
108 Alestas T, Ganceviciene R, Fimmel S, Muller-Decker K, Zouboulis CC. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med. 2006; 84 75-87
109 Akimoto N, Sato T, Iwata C, Koshizuka M, Shibata F, Nagai A, Sumida M, Ito A. Expression of perilipin A on the surface of lipid droplets increases along with the differentiation of hamster sebocytes in vivo and in vitro. J Invest Dermatol. 2005; 124 1127-1133
110 Kim MJ, Deplewski D, Ciletti N, Michel S, Reichert U, Rosenfield RL. Limited cooperation between peroxisome proliferator-activated receptors and retinoid X receptor agonists in sebocyte growth and development. Mol Genet Metab. 2001; 74 362-369
111 Downie MM, Sanders DA, Maier LM, Stock DM, Kealey T. Peroxisome proliferator-activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro. Br J Dermatol. 2004; 151 766-775
112 Mao-Qiang M, Fowler AJ, Schmuth M, Lau P, Chang S, Brown BE, Moser AH, Michalik L, Desvergne B, Wahli W, Li M, Metzger D, Chambon PH, Elias PM, Feingold KR. Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. J Invest Dermatol. 2004; 123 305-312
113 Rosenfield RL, Kentsis A, Deplewski D, Ciletti N. Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors. J Invest Dermatol. 1999; 112 226-232
114 Westergaard M, Henningsen J, Svendsen ML, Johansen C, Jensen UB, Schroder HD, Kratchmarova I, Berge RK, Iversen L, Bolund L, Kragballe K, Kristiansen K. Modulation of keratinocyte gene expression and differentiation by PPAR-selective ligands and tetradecylthioacetic acid. J Invest Dermatol. 2001; 116 702-712
115 Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development. Endocr Rev. 2000; 21 363-392
116 Makrantonaki E, Zouboulis CC. Testosterone metabolism to 5-alpha-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferators-activated receptor ligand linoleic acid in human sebocytes. Br J Dermatol. 2006; , in press
117 Wrobel A, Seltmann H, Fimmel S, Muller-Decker K, Tsukada M, Bogdanoff B, Mandt N, Blume-Peytavi U, Orfanos CE, Zouboulis CC. Differentiation and apoptosis in human immortalized sebocytes. J Invest Dermatol. 2003; 120 175-181
118 Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. Ppar gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999; 4 611-617
119 Zouboulis CC, Nestoris S, Adler YD, Orth M, Orfanos CE, Picardo M, Camera E, Cunliffe WJ. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003; 139 668-670
120 Torma H, Karlsson T, Michaelsson G, Rollman O, Vahlquist A. Decreased mRNA levels of retinoic acid receptor alpha, retinoid X receptor alpha and thyroid hormone receptor alpha in lesional psoriatic skin. Acta Derm Venereol. 2000; 80 4-9
121 Karlsson T, Rollman O, Vahlquist A, Torma H. Immunofluorescence localization of nuclear retinoid receptors in psoriasis versus normal human skin. Acta Derm Venereol. 2004; 84 363-369
122 Rivier M, Safonova I, Lebrun P, Griffiths CE, Ailhaud G, Michel S. Differential expression of peroxisome proliferator-activated receptor subtypes during the differentiation of human keratinocytes. J Invest Dermatol. 1998; 111 1116-1121
123 Feng S, Lin L, Wu Q, Zhou W, Shao C. Study on the expression of RXRalpha in patients with psoriasis vulgaris. Eur J Dermatol. 2006; 16 33-38
124 Elder JT, Fisher GJ, Zhang QY, Eisen D, Krust A, Kastner P, Chambon P, Voorhees JJ. Retinoic acid receptor gene expression in human skin. J Invest Dermatol. 1991; 96 425-433
125 Reichrath J, Munssinger T, Kerber A, Rochette EC, Chambon P, Bahmer FA, Baum HP. In situ detection of retinoid-X receptor expression in normal and psoriatic human skin. Br J Dermatol. 1995; 133 168-175
126 Jensen T, Sorensen S, Solvsten H, Kragballe K. The vitamin d3 receptor and retinoid X receptors in psoriatic skin: the receptor levels correlate with the receptor binding to DNA. Br J Dermatol. 1998; 138 225-228
127 Westergaard M, Henningsen J, Johansen C, Rasmussen S, Svendsen ML, Jensen UB, Schroder HD, Staels B, Iversen L, Bolund L, Kragballe K, Kristiansen K. Expression and localization of peroxisome proliferator-activated receptors and nuclear factor kappaB in normal and lesional psoriatic skin. J Invest Dermatol. 2003; 121 1104-1117
128 Thacher SM, Vasudevan J, Tsang KY, Nagpal S, Chandraratna RA. New dermatological agents for the treatment of psoriasis. J Med Chem. 2001; 44 281-297
129 Kragballe K, Austad J, Barnes L, Bibby A, de la Brassinne M, Cambazard F, Fleming C, Heikkila H, Jolliffe D, Peyri J, Svensson A, Toole J, Wozel G. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol. 2006; 154 1155-1160
130 Kragballe K, Barnes L, Hamberg KJ, Hutchinson P, Murphy F, Moller S, Ruzicka T, Van De Kerkhof PC. Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis: tolerability and efficacy. Br J Dermatol. 1998; 139 649-654
131 Vahlquist A, Torma H, Carlsson B. Inefficacy of topical thyroid hormone analogue THAC in plaque psoriasis: results of a double-blind placebo-controlled trial. Br J Dermatol. 2004; 151 489-491
132 Kuenzli S, Saurat JH. Effect of topical PPARbeta/delta and PPARgamma agonists on plaque psoriasis. A pilot study. Dermatology. 2003; 206 252-256
133 Ellis CN, Varani J, Fisher GJ, Zeigler ME, Pershadsingh HA, Benson SC, Chi Y, Kurtz TW. Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation. Arch Dermatol. 2000; 136 609-616
134 Venkatraman MS, Chittiboyina A, Meingassner J, Ho CI, Varani J, Ellis CN, Avery MA, Pershadsingh HA, Kurtz TW, Benson SC. Alpha-lipoic acid-based ppargamma agonists for treating inflammatory skin diseases. Arch Dermatol Res. 2004; 296 97-104
135 Robertshaw H, Friedmann PS. Pioglitazone: a promising therapy for psoriasis. Br J Dermatol. 2005; 152 189-191
136 Bongartz T, Coras B, Vogt T, Scholmerich J, Muller-Ladner U. Treatment of active psoriatic arthritis with the ppargamma ligand pioglitazone: an open-label pilot study. Rheumatology (Oxford). 2005; 44 126-129
137 Christophers E. Comorbidities in psoriasis. J Eur Acad Dermatol Venereol. 2006; 20 52-55
138 Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006; 296 1735-1741
139 Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res. 2006; , in press
140 Butt C, Gladman D, Rahman P. PPAR-gamma gene polymorphisms and psoriatic arthritis. J Rheumatol. 2006; 33 1631-1633
141 Mossner R, Kaiser R, Matern P, Kruger U, Westphal GA, Brockmoller J, Ziegler A, Neumann C, Konig IR, Reich K. Variations in the genes encoding the peroxisome proliferator-activated receptors alpha and gamma in psoriasis. Arch Dermatol Res. 2004; 296 1-5
142 Sheu MY, Fowler AJ, Kao J, Schmuth M, Schoonjans K, Auwerx J, Fluhr JW, Man MQ, Elias PM, Feingold KR. Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models. J Invest Dermatol. 2002; 118 94-101
143 Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, Collins JL, Willson TM, Mangelsdorf DJ, Elias PM, Feingold KR. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol. 2003; 120 246-255
144 Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci USA. 2005; 102 14795-14800
145 Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol. 1999; 155 1137-1146
146 Hunt TK. Vitamin A and wound healing. J Am Acad Dermatol. 1986; 15 817-821
147 Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg. 1968; 167 324-238
148 Reed BR, Clark RA. Cutaneous tissue repair: practical implications of current knowledge. II. J Am Acad Dermatol. 1985; 13 919-941
149 Beer HD, Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm. 2000; 59 217-239
150 Grose R, Werner S, Kessler D, Tuckermann J, Huggel K, Durka S, Reichardt HM, Werner S. A role for endogenous glucocorticoids in wound repair. EMBO Rep. 2002; 3 575-582
151 Ashcroft GS, Mills SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest. 2002; 110 615-624
152 Slight SH, Chilakamarri VK, Nasr S, Dhalla AK, Ramires FJ, Sun Y, Ganjam VK, Weber KT. Inhibition of tissue repair by spironolactone: role of mineralocorticoids in fibrous tissue formation. Mol Cell Biochem. 1998; 189 47-54
153 Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, Metzger D, Chambon P, Duboule D, Wahli W. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice. J Cell Biol. 2001; 154 799-814
154 Tan NS, Michalik L, Di-Poi N, Desvergne B, Wahli W. Critical roles of the nuclear receptor PPARbeta (peroxisome-proliferator-activated receptor beta) in skin wound healing. Biochem Soc Trans. 2004; 32 97-102
155 Gilchrest BA. A review of skin ageing and its medical therapy. Br J Dermatol. 1996; 135 867-875
156 Tsukahara K, Nakagawa H, Moriwaki S, Kakuo S, Ohuchi A, Takema Y, Imokawa G. Ovariectomy is sufficient to accelerate spontaneous skin ageing and to stimulate ultraviolet irradiation-induced photoageing of murine skin. Br J Dermatol. 2004; 151 984-994
157 Brincat M, Moniz CJ, Studd JW, Darby A, Magos A, Emburey G, Versi E. Long-term effects of the menopause and sex hormones on skin thickness. Br J Obstet Gynaecol. 1985; 92 256-259
158 Brincat M, Versi E, O'Dowd T, Moniz CF, Magos A, Kabalan S, Studd JW. Skin collagen changes in post-menopausal women receiving oestradiol gel. Maturitas. 1987; 9 1-5
159 Kanda N, Watanabe S. 17beta-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression. J Invest Dermatol. 2004; 123 319-328
160 Rauramo L, Punnonen R. Effect of oral estrogen treatment with estriol succinate on the skin of castrated women. Z Haut Geschlechtskr. 1969; 44 463-470
161 Dunn LB, Damesyn M, Moore AA, Reuben DB, Greendale GA. Does estrogen prevent skin aging? Results from the First National Health and Nutrition Examination Survey (nhanes i). Arch Dermatol. 1997; 133 339-342
162 Pierard-Franchimont C, Letawe C, Goffin V, Pierard GE. Skin water-holding capacity and transdermal estrogen therapy for menopause: a pilot study. Maturitas. 1995; 22 151-154
163 Callens A, Vaillant L, Lecomte P, Berson M, Gall Y, Lorette G. Does hormonal skin aging exist? A study of the influence of different hormone therapy regimens on the skin of postmenopausal women using non-invasive measurement techniques. Dermatology. 1996; 193 289-294
164 Sator PG, Schmidt JB, Sator MO, Huber JC, Honigsmann H. The influence of hormone replacement therapy on skin ageing: a pilot study. Maturitas. 2001; 39 43-55
165 Castelo-Branco C, Duran M, Gonzalez-Merlo J. Skin collagen changes related to age and hormone replacement therapy. Maturitas. 1992; 15 113-119
166 Varila E, Rantala I, Oikarinen A, Risteli J, Reunala T, Oksanen H, Punnonen R. The effect of topical oestradiol on skin collagen of postmenopausal women. Br J Obstet Gynaecol. 1995; 102 985-989
167 Varila E, Wahlstrom T, Rauramo I. A 5-year follow-up study on the use of a levonorgestrel intrauterine system in women receiving hormone replacement therapy. Fertil Steril. 2001; 76 969-973
168 Sauerbronn AV, Fonseca AM, Bagnoli VR, Saldiva PH, Pinotti JA. The effects of systemic hormonal replacement therapy on the skin of postmenopausal women. Int J Gynaecol Obstet. 2000; 68 35-41
169 Punnonen R, Vaajalahti P, Teisala K. Local oestriol treatment improves the structure of elastic fibers in the skin of postmenopausal women. Ann Chir Gynaecol Suppl. 1987; 202 39-41
170 Haapasaari KM, Raudaskoski T, Kallioinen M, Suvanto-Luukkonen E, Kauppila A, Laara E, Risteli J, Oikarinen A. Systemic therapy with estrogen or estrogen with progestin has no effect on skin collagen in postmenopausal women. Maturitas. 1997; 27 153-162
171 Deslypere JP, Vermeulen A. Aging and tissue androgens. J Clin Endocrinol Metab. 1981; 53 430-434
172 Blouin K, Despres JP, Couillard C, Tremblay A, Prud'homme D, Bouchard C, Tchernof A. Contribution of age and declining androgen levels to features of the metabolic syndrome in men. Metabolism. 2005; 54 1034-1040
173 Black MM, Shuster S, Bottoms E. Osteoporosis, skin collagen, and androgen. Br Med J. 1970; 4 773-774
174 Bullough WS, van OG. The mitogenic actions of testosterone propionate and of oestrone on the epidermis of the adult male mouse. Acta Endocrinol (Copenh). 1950; 4 291-305
175 Ebling FJ. The action of testosterone on the sebaceous glands and epidermis in castrated and hypophysectomized male rats. J Endocrinol. 1957; 15 297-306
176 Antebi A, Yeh WH, Tait D, Hedgecock EM, Riddle DL. DAF-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. Elegans. Genes Dev. 2000; 14 1512-1527
177 Snow MI, Larsen PL. Structure and expression of DAF-12: a nuclear hormone receptor with three isoforms that are involved in development and aging in Caenorhabditis elegans. Biochim Biophys Acta. 2000; 1494 104-116
178 Mooijaart SP, Brandt BW, Baldal EA, Pijpe J, Kuningas M, Beekman M, Zwaan BJ, Slagboom PE, Westendorp RG, van Heemst DC. Elegans DAF-12, nuclear hormone receptors and human longevity and disease at old age. Ageing Res Rev. 2005; 4 351-371
179 Gerin I, Dolinsky VW, Shackman JG, Kennedy RT, Chiang SH, Burant CF, Steffensen KR, Gustafsson JA, MacDougald OA. LXRbeta is required for adipocyte growth, glucose homeostasis, and beta cell function. J Biol Chem. 2005; 280 23024-23031
180 Hanley K, Komuves LG, Bass NM, He SS, Jiang Y, Crumrine D, Appel R, Friedman M, Bettencourt J, Min K, Elias PM, Williams ML, Feingold KR. Fetal epidermal differentiation and barrier development in vivo is accelerated by nuclear hormone receptor activators. J Invest Dermatol. 1999; 113 788-795
181 Enderlin V, Alfos S, Pallet V, Garcin H, Azais-Braesco V, Jaffard R, Higueret P. Aging decreases the abundance of retinoic acid (RAR) and triiodothyronine (TR) nuclear receptor mRNA in rat brain: effect of the administration of retinoids. FEBS Lett. 1997; 412 629-632
182 Enderlin V, Pallet V, Alfos S, Dargelos E, Jaffard R, Garcin H, Higueret P. Age-related decreases in mRNA for brain nuclear receptors and target genes are reversed by retinoic acid treatment. Neurosci Lett. 1997; 229 125-129
183 Watson RE, Arjuna Ratnayaka J, Brooke RC, Yee-Sit-Yu S, Ancian P, Griffiths CE. Retinoic acid receptor alpha expression and cutaneous ageing. Mech Ageing Dev. 2004; 125 465-473
184 Wang Z, Boudjelal M, Kang S, Voorhees JJ, Fisher GJ. Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. Nat Med. 1999; 5 418-422
185 Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang S, Chung JH, Wang ZQ, Datta SC, Fisher GJ, Voorhees JJ. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol. 2000; 114 480-486
186 Bailly C, Dreze S, Asselineau D, Nusgens B, Lapiere CM, Darmon M. Retinoic acid inhibits the production of collagenase by human epidermal keratinocytes. J Invest Dermatol. 1990; 94 47-51
187 Varani J, Perone P, Griffiths CE, Inman DR, Fligiel SE, Voorhees JJ. All-trans retinoic acid (RA) stimulates events in organ-cultured human skin that underlie repair. Adult skin from sun-protected and sun-exposed sites responds in an identical manner to RA while neonatal foreskin responds differently. J Clin Invest. 1994; 94 1747-1756
188 Kligman AM, Fulton Jr JE, Plewig G. Topical vitamin A acid in acne vulgaris. Arch Dermatol. 1969; 99 469-476
189 Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol. 1986; 15 836-859
190 Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin. A double-blind vehicle-controlled study. JAMA. 1988; 259 527-532
191 Schwartz E, Cruickshank FA, Mezick JA, Kligman LH. Topical all-trans retinoic acid stimulates collagen synthesis in vivo. J Invest Dermatol. 1991; 96 975-978
192 Woodley DT, Zelickson AS, Briggaman RA, Hamilton TA, Weiss JS, Ellis CN, Voorhees JJ. Treatment of photoaged skin with topical tretinoin increases epidermal-dermal anchoring fibrils. A preliminary report. JAMA. 1990; 263 3057-3059
193 Watson RE, Craven NM, Kang S, Jones CJ, Kielty CM, Griffiths CE. A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents. J Invest Dermatol. 2001; 116 672-678

Correspondence

M. Schmuth

Department of Dermatology·Innsbruck Medical University

Anichstr. 35

6020 Innsbruck

Phone: +43/512/504 29 971

Fax: +43/512/504 22 99 0

Email: matthias.schmuth@i-med.ac.at