title: Heat Shock Protein 90 Inhibitor Decreases Collagen Synthesis of Keloid Fibroblasts and Attenuates the Extracellular Matrix on the Keloid Spheroid Model.
abstract: 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.
  
  
  CONCLUSIONS
  These results suggest that the antifibrotic action of heat-shock protein 90 inhibitors such as 17-AAG may have therapeutic effects on keloids.
authors: Seoul, Republic of Korea From the Institute for Human Tissue Restoration, the Department of Plastic and Reconstructive Surgery, Department of Dermatology, the Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine; and the Department of Bioengineering, College of Engineering, Hanyang University.
authors: Won Jai
authors: WJ
authors: Lee
authors: Ju Hee
authors: JH
authors: Lee
authors: Hyo Min
authors: HM
authors: Ahn
authors: Seung Yong
authors: SY
authors: Song
authors: Yong Oock
authors: YO
authors: Kim
authors: Dae Hyun
authors: DH
authors: Lew
authors: Chae-Ok
authors: CO
authors: Yun
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D024061:Collagen Type III / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007627:Keloid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D015415:Biomarkers; D024042:Collagen Type I; D024061:Collagen Type III; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016212:Transforming Growth Factor beta; C112765:tanespimycin