Related Experiment Video
Updated: Aug 19, 2025
Y-27632 Enriches the Yield of Human Melanocytes from Adult Skin Tissues
Published on: July 8, 2020
Reversion of glucocorticoid-induced senescence and collagen synthesis decrease by LY294002 is mediated through p38 in
Quoc-Vu Le1,2, Su-Ying Wen3,4, Chih-Jung Chen5
1Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ROC.
Abstract:
Glucocorticoids (GCs) are the most common treatment for inflammatory skin disorders; however, they show several adverse side effects, including atrophy and collagen decrease following chronic treatment. In particular, transcription factors and p38 signaling for collagen synthesis have been shown to be suppressed by the active glucocorticoid receptor (GR). LY294002 (LY), a phosphoinositide 3-kinase (PI3K) inhibitor, has been reported to protect keratinocytes in epidermis against GC-induced hypoplasia; however, its protective effect in dermis remains unclear. Furthermore, clobetasol propionate (CP) is the most used commercial synthetic GC, yet studies on how CP causes side effects in dermal fibroblasts are limited. In this study, dermal atrophy was modeled using CP in human dermal fibroblasts (HDFs) and C57BL/6 mice. CP treatment significantly upregulated FK506 binding protein 5 (FKBP51), an atrophy marker (2.4 ± 0.25 and 3.3 ± 0.3 fold in in vitro and in vivo, respectively), phosphorylated GR (1.96 ± 0.08 and 2.29 ± 0.25 fold in in vitro and in vivo, respectively), decreased fibroblast proliferation (82.71 ± 1.95% in in vitro), reduced collagen synthesis (0.36 ± 0.05 and 0.3 ± 0.1 fold in in vitro and in vivo, respectively), and induced aging, all of which were reversed by LY treatment (from 1.43 ± 0.08 to 2.8 ± 0.12 fold) without showing growth inhibition and exerting the anti-inflammation of CP. Interestingly, the protective effect of LY was dose-dependently reversed by treatment with a p38 inhibitor and reached 2.9 ± 0.15 fold at dose 20 µM. Taken together, our results demonstrate that LY reduced CP-induced upregulation of the atrophy marker FKBP51, GR phosphorylation, and GR nuclear translocation via the activation of p38, whilst maintaining the anti-inflammatory effect of glucocorticoids.
Insights
Glucocorticoids cause skin atrophy by suppressing collagen. LY294002 (LY) protects against this by activating p38 signaling, reversing atrophy markers and collagen loss without inhibiting anti-inflammatory effects.
Area of Science:
- Dermatology and Molecular Biology
- Investigating the molecular mechanisms of skin aging and therapeutic interventions.
Background:
- Glucocorticoids (GCs) are primary treatments for inflammatory skin conditions but cause adverse effects like atrophy and collagen reduction.
- The active glucocorticoid receptor (GR) suppresses collagen synthesis via transcription factors and p38 signaling.
- LY294002 (LY), a PI3K inhibitor, shows epidermal protection against GCs, but its dermal effects are unknown.
Purpose of the Study:
- To investigate the protective effects of LY294002 (LY) against clobetasol propionate (CP)-induced dermal atrophy in human dermal fibroblasts and mice.
- To elucidate the role of p38 signaling in LY's protective mechanism against GC-induced skin aging.
Main Methods:
- Dermal atrophy was modeled using clobetasol propionate (CP) in human dermal fibroblasts (HDFs) and C57BL/6 mice.
- Key markers including FKBP51, phosphorylated GR, fibroblast proliferation, and collagen synthesis were measured.
- The effect of LY294002 (LY) and its interaction with p38 inhibitors were analyzed.
Main Results:
- CP significantly upregulated the atrophy marker FKBP51 and phosphorylated GR, decreased fibroblast proliferation, and reduced collagen synthesis.
- LY treatment reversed these CP-induced changes, mitigating dermal atrophy and aging without inhibiting cell growth.
- LY's protective effect was dose-dependently reversed by p38 inhibition, indicating p38 activation is crucial for LY's action.
Conclusions:
- LY294002 mitigates glucocorticoid-induced dermal atrophy by activating p38 signaling, which counteracts FKBP51 upregulation and GR phosphorylation.
- This mechanism preserves collagen synthesis and fibroblast proliferation while maintaining the anti-inflammatory properties of glucocorticoids.
- LY represents a potential therapeutic strategy to prevent or treat glucocorticoid-induced skin atrophy.
More Related Videos
07:32Human Ex vivo Wound Model and Whole-Mount Staining Approach to Accurately Evaluate Skin Repair
Published on: February 17, 2021
10:05Stimulation of Stem Cell Niches and Tissue Regeneration in Mouse Skin by Switchable Protoporphyrin IX-Dependent Photogeneration of Reactive Oxygen Species In Situ
Published on: May 8, 2020
Related Concept Videos
01:12Renewal of Skin Epidermal Stem Cells
01:19Clinical Applications of Epidermal Stem Cells
01:12GPCR Desensitization
01:19The Effect of Aging on Tissues
01:23Tissue Renewal without Stem Cells
However, failure of such a system...