EMBO Molecular Medicine | |
REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids | |
Gleb Baida1  Pankaj Bhalla1  Kirill Kirsanov3  Ekaterina Lesovaya3  Marianna Yakubovskaya3  Kit Yuen1  Shuchi Guo1  Robert M Lavker1  Ben Readhead2  Joel T Dudley2  | |
[1] Department of Dermatology, Northwestern University, Chicago, IL, USA;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;N. Blokhin Cancer Research Center, RAMS, Moscow, Russia | |
关键词: glucocorticoid; glucocorticoid receptor; mTOR; REDD1; skin atrophy; | |
DOI : 10.15252/emmm.201404601 | |
来源: Wiley | |
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【 摘 要 】
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. Cutaneous atrophy is the major adverse effect of topical glucocorticoids (GC). In a preclinical setting, knockdown of the stress-inducible mTOR inhibitor REDD1 preserves the anti-inflammatory effect of GC while protecting from atrophy.Abstract
Synopsis
【 授权许可】
CC BY
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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