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Open Access 01-10-2014 | Original Paper

Calcipotriol counteracts betamethasone-induced decrease in extracellular matrix components related to skin atrophy

Authors: Hanne Norsgaard, Sandrine Kurdykowski, Pascal Descargues, Tatiana Gonzalez, Troels Marstrand, Georg Dünstl, Mads Røpke

Published in: Archives of Dermatological Research | Issue 8/2014

Abstract

The calcipotriol/betamethasone dipropionate fixed-combination gel is widely used for topical treatment of psoriasis vulgaris. It has been hypothesized that calcipotriol counteracts glucocorticoid-induced skin atrophy which is associated with changes in the extracellular matrix (ECM). To elucidate the combined effects of calcipotriol and betamethasone on key ECM components, a comparative study to the respective mono-treatments was carried out. The effect on collagen I synthesis, matrix metalloproteinase (MMP) secretion, and hyaluronic acid (HA) production was investigated in primary human fibroblast and keratinocyte cultures as well as in a human skin explant model. We show that calcipotriol counteracts betamethasone-induced suppression of collagen I synthesis. Similarly, calcipotriol and betamethasone have opposing effects on MMP expression in both fibroblasts and keratinocytes. Moreover, calcipotriol is able to restore betamethasone-impaired HA synthesis in keratinocytes and prevent betamethasone-induced epidermal thinning in minipigs upon treatment with the calcipotriol/betamethasone gel. In summary, our results show for the first time in primary human skin cultures that calcipotriol reduces early signs of betamethasone-induced skin atrophy by modulation of key ECM components. These results indicate that the calcipotriol component of the fixed-combination gel counteracts the atrophogenic effects of betamethasone on the skin.

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Averbeck M, Gebhardt C, Anderegg U, Simon JC (2010) Suppression of hyaluronan synthase 2 expression reflects the atrophogenic potential of glucocorticoids. Exp Dermatol 19:757–759PubMedCrossRef

Bauer EA, Kronberger A, Valle KJ, Jeffrey JJ, Eisen AZ (1985) Glucocorticoid modulation of collagenase expression in human skin fibroblast cultures. Evidence for pre-translational inhibition. Biochim Biophys Acta 825:227–235PubMedCrossRef

Castela E, Archier E, Devaux S, Gallini A, Aractingi S, Cribier B et al (2012) Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. J Eur Acad Dermatol Venereol 26(Suppl 3):47–51PubMedCrossRef

Clark SD, Kobayashi DK, Welgus HG (1987) Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts. J Clin Invest 80:1280–1288PubMedCrossRefPubMedCentral

Cutroneo KR, Rokowski R, Counts DF (1981) Glucocorticoids and collagen synthesis: comparison of in vivo and cell culture studies. Coll Relat Res 1:557–568PubMedCrossRef

Dai G, Freudenberger T, Zipper P, Melchior A, Grether-Beck S, Rabausch B et al (2007) Chronic ultraviolet B irradiation causes loss of hyaluronic acid from mouse dermis because of downregulation of hyaluronic acid synthases. Am J Pathol 171:1451–1461PubMedCrossRefPubMedCentral

Delforno C, Holt PJ, Marks R (1978) Corticosteroid effect on epidermal cell size. Br J Dermatol 98:619–623PubMedCrossRef

Gebhardt C, Averbeck M, Diedenhofen N, Willenberg A, Anderegg U, Sleeman JP et al (2010) Dermal hyaluronan is rapidly reduced by topical treatment with glucocorticoids. J Invest Dermatol 130:141–149PubMedCrossRef

Gniadecki R (1996) Stimulation versus inhibition of keratinocyte growth by 1,25-Dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 106:510–516PubMedCrossRef

10.

Gniadecki R, Gniadecka M, Serup J (1994) Inhibition of glucocorticoid-induced epidermal and dermal atrophy with KH 1060—a potent 20-epi analogue of 1,25-dihydroxyvitamin D3. Br J Pharmacol 113:439–444PubMedCrossRefPubMedCentral

11.

Gniadecki R, Gniadecka M, Serup J (1995) The effects of KH 1060, a potent 20-epi analogue of the vitamin D3 hormone, on hairless mouse skin in vivo. Br J Dermatol 132:841–852PubMedCrossRef

12.

Haugen JD, Pittelkow MR, Zinsmeister AR, Kumar R (1996) 1 alpha,25-dihydroxyvitamin D3 inhibits normal human keratinocyte growth by increasing transforming growth factor beta 2 release. Biochem Biophys Res Commun 229:618–623PubMedCrossRef

13.

Hein R, Korting HC, Mehring T (1994) Differential effect of medium potent nonhalogenated double-ester-type and conventional glucocorticoids on proliferation and chemotaxis of fibroblasts in vitro. Skin Pharmacol 7:300–306PubMedCrossRef

14.

Hong SP, Oh Y, Jung M, Lee S, Jeon H, Cho MY et al (2010) Topical calcitriol restores the impairment of epidermal permeability and antimicrobial barriers induced by corticosteroids. Br J Dermatol 162:1251–1260PubMedCrossRef

15.

Kao JS, Fluhr JW, Man MQ, Fowler AJ, Hachem JP, Crumrine D et al (2003) Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol 120:456–464PubMedCrossRef

16.

Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P et al (2006) Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med 3:e493PubMedCrossRefPubMedCentral

17.

Kolbe L, Kligman AM, Schreiner V, Stoudemayer T (2001) Corticosteroid-induced atrophy and barrier impairment measured by non-invasive methods in human skin. Skin Res Technol 7:73–77PubMedCrossRef

18.

Koob TJ, Jeffrey JJ, Eisen AZ (1974) Regulation of human skin collagenase activity by hydrocortisone and dexamethasone in organ culture. Biochem Biophys Res Commun 61:1083–1088PubMedCrossRef

19.

Kragballe K, Austad J, Barnes L, Bibby A, de la Brassinne M, Cambazard F et al (2006) Efficacy results of a 52-week, randomised, double-blind, safety study of a calcipotriol/betamethasone dipropionate two-compound product (Daivobet/Dovobet/Taclonex) in the treatment of psoriasis vulgaris. Dermatology 213:319–326PubMedCrossRef

20.

Kylmaniemi M, Oikarinen A, Oikarinen K, Salo T (1996) Effects of dexamethasone and cell proliferation on the expression of matrix metalloproteinases in human mucosal normal and malignant cells. J Dent Res 75:919–926PubMedCrossRef

21.

Meisler N, Keefer KA, Ehrlich HP, Yager DR, Myers-Parrelli J, Cutroneo KR (1997) Dexamethasone abrogates the fibrogenic effect of transforming growth factor-beta in rat granuloma and granulation tissue fibroblasts. J Invest Dermatol 108:285–289PubMedCrossRef

22.

Meran S, Luo DD, Simpson R, Martin J, Wells A, Steadman R et al (2011) Hyaluronan facilitates transforming growth factor-beta1-dependent proliferation via CD44 and epidermal growth factor receptor interaction. J Biol Chem 286:17618–17630PubMedCrossRefPubMedCentral

23.

Oikarinen A, Autio P, Kiistala U, Risteli L, Risteli J (1992) A new method to measure type I and III collagen synthesis in human skin in vivo: demonstration of decreased collagen synthesis after topical glucocorticoid treatment. J Invest Dermatol 98:220–225PubMedCrossRef

24.

Oikarinen A, Vuorio E, Vuorio T (1989) Comparison of the effects of dexamethasone and 13-cis-retinoic acid on connective tissue biosynthesis in human skin fibroblasts. Arch Dermatol Res 281:273–278PubMedCrossRef

25.

Oyama N, Iwatsuki K, Satoh M, Akiba H, Kaneko F (2000) Dermal fibroblasts are one of the therapeutic targets for topical application of 1alpha,25-dihydroxyvitamin D3: the possible involvement of transforming growth factor-beta induction. Br J Dermatol 143:1140–1148PubMedCrossRef

26.

Saarni H, Hopsu-Havu VK (1978) The decrease of hyaluronate synthesis by anti-inflammatory steroids in vitro. Br J Dermatol 98:445–449PubMedCrossRef

27.

Sarnstrand B, Brattsand R, Malmstrom A (1982) Effect of glucocorticoids on glycosaminoglycan metabolism in cultured human skin fibroblasts. J Invest Dermatol 79:412–417PubMedCrossRef

28.

Schoepe S, Schacke H, Bernd A, Zoller N, Asadullah K (2010) Identification of novel in vitro test systems for the determination of glucocorticoid receptor ligand-induced skin atrophy. Skin Pharmacol Physiol 23:139–151PubMedCrossRef

29.

Segaert S, Ropke M (2013) The biological rationale for use of vitamin d analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Dermatol 12:e129–e137PubMed

30.

Tetlow LC, Woolley DE (1999) The effects of 1 alpha,25-dihydroxyvitamin D(3) on matrix metalloproteinase and prostaglandin E(2) production by cells of the rheumatoid lesion. Arthritis Res 1:63–70PubMedCrossRefPubMedCentral

31.

Traulsen J, Hughes-Formella BJ (2003) The atrophogenic potential and dermal tolerance of calcipotriol/betamethasone dipropionate ointment compared with betamethasone dipropionate ointment. Dermatology 207:166–172PubMedCrossRef

32.

Verrecchia F, Mauviel A (2002) Control of connective tissue gene expression by TGF beta: role of Smad proteins in fibrosis. Curr Rheumatol Rep 4:143–149PubMedCrossRef

33.

Weindl G, Castello F, Schafer-Korting M (2011) Evaluation of anti-inflammatory and atrophogenic effects of glucocorticoids on reconstructed human skin. Altern Lab Anim 39:173–187PubMed

34.

Zhang W, Watson CE, Liu C, Williams KJ, Werth VP (2000) Glucocorticoids induce a near-total suppression of hyaluronan synthase mRNA in dermal fibroblasts and in osteoblasts: a molecular mechanism contributing to organ atrophy. Biochem J 349:91–97PubMedCrossRefPubMedCentral

35.

Zoller NN, Kippenberger S, Thaci D, Mewes K, Spiegel M, Sattler A et al (2008) Evaluation of beneficial and adverse effects of glucocorticoids on a newly developed full-thickness skin model. Toxicol In Vitro 22:747–759PubMedCrossRef

Title: Calcipotriol counteracts betamethasone-induced decrease in extracellular matrix components related to skin atrophy
Authors: Hanne Norsgaard
Sandrine Kurdykowski
Pascal Descargues
Tatiana Gonzalez
Troels Marstrand
Georg Dünstl
Mads Røpke
Publication date: 01-10-2014
Publisher: Springer Berlin Heidelberg
Published in: Archives of Dermatological Research / Issue 8/2014
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI: https://doi.org/10.1007/s00403-014-1485-3

At a glance: The STEP trials

Springer Medicine

Calcipotriol counteracts betamethasone-induced decrease in extracellular matrix components related to skin atrophy

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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