Investigation of the Skin Thinning Effect of Prednicarbate and Other Corticoids in Mouse Skin

Lubach, D; Kietzmann, Manfred

doi:10.1159/000210774

Cited by 10 publications

(3 citation statements)

References 8 publications

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“…Skin atrophy involves all skin compartments, that is, epidermis, dermis, sebaceous glands, and subcutaneous (s.c.) fat. Typical epidermal changes include a reduction in thickness, decreased number and size of keratinocytes, diminished stratum corneum and intercellular lipid lamella (Jablonska et al , ; Lehmann et al , ; Zheng et al , ; Lubach & Kietzmann, ; Schoepe et al , ). These changes are combined with an altered orientation and packing of collagen and elastin fibers, and decreased cellularity in the dermis (Lehmann et al , ; Schoepe et al , ).…”

Section: Introductionmentioning

confidence: 99%

REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids

et al. 2014

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Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress-inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down-regulation of genes involved in anti-inflammatory glucocorticoid response was strikingly similar in wild-type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid-dependent and glucocorticoid-independent atrophy. Importantly, the lack of REDD1 did not diminish the anti-inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid-based therapies.

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Section: Introductionmentioning

confidence: 99%

REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids

et al. 2014

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“…One of the most prominent side effects of glucocorticoid therapy is skin atrophy that affects different skin components and compromises the barrier function of the skin. Glucocorticoid-induced skin atrophy is characterized by a reduction in epidermal thickness, a decreased number of keratinocytes, diminished stratum corneum intercellular lipid lamella, loss of ground substance, altered orientation and packing of collagen and elastin fibers combined with a decreased cellularity in dermis, elimination of subcutaneous fat, and loss of mast ORIGINAL ARTICLE cells (Jablonska et al, 1979;Lehmann et al, 1983;Zheng et al, 1984;Lavker et al, 1986;Lubach and Kietzmann, 1988;Schoepe et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Epithelial Cells in the Hair Follicle Bulge do not Contribute to Epidermal Regeneration after Glucocorticoid-Induced Cutaneous Atrophy

Chebotaev

Yemelyanov

Lavker

et al. 2007

Journal of Investigative Dermatology

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One of the major adverse effects of glucocorticoid therapy is cutaneous atrophy, often followed by the development of resistance to steroids. It is accepted that epithelial stem cells (SCs) located in the hair follicle bulge divide during times of epidermal proliferative need. We determined whether follicular epithelial SCs and their transit amplifying progeny were stimulated to proliferate in response to the chronic application of glucocorticoid fluocinolone acetonide (FA). After first two applications of FA, keratinocyte proliferation in the interfollicular epidermis (IFE) and hair follicles was minimal and resulted in significant epidermal hypoplasia. We observed that a 50% depletion of the interfollicular keratinocyte population triggered a proliferative response. Unexpectedly, less than 2% of the proliferating keratinocytes were located in the bulge region of the hair follicle, whereas 82% were in IFE. It is known that cell desensitization to glucocorticoids is mediated via temporary decrease of glucocorticoid receptor (GR) expression. We found that GR expression was significantly decreased in IFE keratinocytes after each FA treatment. In contrast, many bulge keratinocytes retained GR in the nucleus. Our results indicate that bulge keratinocytes, including follicular SCs, are more sensitive to the antiproliferative effect of glucocorticoids than basal keratinocytes, possibly due to the incomplete process of desensitization.

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“…However, 10-substituted triacetoxyanthracenes such as the cinnamic acid derivative 37 [102] (Fig. 8) have been shown to have activity comparable to anthralin and superior to 3 and butantrone (4) in the mouse tail assay [103], based on the incorporation of thymidine triphosphate into DNA, inhibition of ornithine decarboxylase activity, incorporation rates of leucine, and histological investigations. It was anticipated that modifying the critical C-10 position of anthralin might provide agents with diminished oxygen-radical formation and stabilized 1,8-dihydroxy-9(10H)-anthracenone pharmacophore.…”

Section: Substitution At the Oxygen Functionsmentioning

confidence: 99%

Current Status and Recent Developments in Anthracenone Antipsoriatics

Müller

2000

CPD

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Treatment of psoriasis is rapidly changing, and there have been dramatic additions such as topical vitamin D analogs and a topical retinoid to the therapeutic armamentarium in recent years. Even though drug therapy is often inadequate and serves only to abate the skin disorder, anthralin of the anthracenone antipsoriatics clears the rash totally. Of all antipsoriatic agents, anthralin has proven to be the most remarkably consistent and time-honored drug for treating the disease. However, anthralin therapy is accompanied by inflammation and staining of the nonaffected skin surrounding a psoriatic lesion. A large body of evidence has shown that the biochemical basis for its mechanism of action at the molecular level is related to its redox chemistry leading to the production of oxygen radicals. These can react with all classes of biological macromolecules and are involved in the principal cellular effects of the anthracenones. This article will focus on current strategies to minimize the potential of skin inflammation by anthralin and the underlying concepts of controlling and manipulating oxygen-radical generation which are essential for the rational design of novel anthracenones. Various studies have shown that by altering the structure of anthralin the in vitro profile can be markedly altered from an only moderate 5-lipoxygenase inhibitor to a more potent inhibitor of this enzyme, which may reflect improved activity against the inflammatory component of psoriasis while the antiproliferative activity is retained. The structural change is also accompanied by significantly diminished oxygen-radical generation and proinflammatory action on the skin. In particular, derivatives bearing a phenylacyl substituent in the critical 10-position of the anthracenone molecule have a favorable overall profile for achieving improved topical therapy of psoriasis.

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Investigation of the Skin Thinning Effect of Prednicarbate and Other Corticoids in Mouse Skin

Cited by 10 publications

References 8 publications

REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids

REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids

Epithelial Cells in the Hair Follicle Bulge do not Contribute to Epidermal Regeneration after Glucocorticoid-Induced Cutaneous Atrophy

Current Status and Recent Developments in Anthracenone Antipsoriatics

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