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Heat Shock Protein 90 Inhibitor Decreases Collagen Synthesis of Keloid Fibroblasts and Attenuates the Extracellular Matrix on the Keloid Spheroid Model

 Lee, Won Jai  ;  Lee, Ju Hee  ;  Ahn, Hyo Min  ;  Song, Seung Yong  ;  Kim, Yong Oock  ;  Lew, Dae Hyun  ;  Yun, Chae-Ok 
 PLASTIC AND RECONSTRUCTIVE SURGERY, Vol.136(3) : 328-337, 2015 
Journal Title
Issue Date
Benzoquinones/pharmacology* ; Benzoquinones/therapeutic use ; Biomarkers/metabolism ; Blotting, Western ; Cells, Cultured ; Collagen Type I/metabolism* ; Collagen Type III/metabolism* ; Enzyme-Linked Immunosorbent Assay ; Extracellular Matrix/drug effects* ; Extracellular Matrix/metabolism ; Fibroblasts/drug effects* ; Fibroblasts/metabolism ; HSP90 Heat-Shock Proteins/antagonists & inhibitors* ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Immunohistochemistry ; Keloid/drug therapy ; Keloid/metabolism* ; Keloid/pathology ; Lactams, Macrocyclic/pharmacology* ; Lactams, Macrocyclic/therapeutic use ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Spheroids, Cellular/drug effects ; Spheroids, Cellular/metabolism ; Spheroids, Cellular/pathology ; Transforming Growth Factor beta/antagonists & inhibitors ; Transforming Growth Factor beta/metabolism
BACKGROUND: The 90-kDa heat-shock protein (heat-shock protein 90) is an abundant cytosolic chaperone, and inhibition of heat-shock protein 90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) compromises transforming growth factor (TGF)-β-mediated transcriptional responses by enhancing TGF-β receptor I and II degradation, thus preventing Smad2/3 activation. In this study, the authors evaluated whether heat-shock protein 90 regulates TGF-β signaling in the pathogenesis and treatment of keloids. METHODS: Keloid fibroblasts were treated with 17-AAG (10 μM), and mRNA levels of collagen types I and III were determined by real-time reverse- transcriptase polymerase chain reaction. Also, secreted TGF-β1 was assessed by enzyme-linked immunosorbent assay. The effect of 17-AAG on protein levels of Smad2/3 complex was determined by Western blot analysis. In addition, in 17-AAG-treated keloid spheroids, the collagen deposition and expression of major extracellular matrix proteins were investigated by means of Masson trichrome staining and immunohistochemistry. RESULTS: The authors found that heat-shock protein 90 is overexpressed in human keloid tissue compared with adjacent normal tissue, and 17-AAG decreased mRNA levels of type I collagen, secreted TGF-ß1, and Smad2/3 complex protein expression in keloid fibroblasts. Masson trichrome staining revealed that collagen deposition was decreased in 17-AAG-treated keloid spheroids, and immunohistochemical analysis showed that expression of collagen types I and III, elastin, and fibronectin was markedly decreased in 17-AAG-treated keloid spheroids. CONCLUSION: These results suggest that the antifibrotic action of heat-shock protein 90 inhibitors such as 17-AAG may have therapeutic effects on keloids.
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1. College of Medicine (의과대학) > Dept. of Plastic and Reconstructive Surgery (성형외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yong Oock(김용욱) ORCID logo https://orcid.org/0000-0002-3756-4809
Song, Seung Yong(송승용) ORCID logo https://orcid.org/0000-0002-3145-7463
Lew, Dae Hyun(유대현)
Lee, Won Jai(이원재) ORCID logo https://orcid.org/0000-0003-3056-0503
Lee, Ju Hee(이주희) ORCID logo https://orcid.org/0000-0002-1739-5956
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