title: FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis.
abstract: BACKGROUND
  Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).
  
  
  OBJECTIVE
  To assess the expression and function of FKBP10 in IPF.
  
  
  METHODS
  We assessed FKBP10 expression in bleomycin-induced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-β1, was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.
  
  
  RESULTS
  FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68(+) macrophages. Transforming growth factor-β1, but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and α-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.
  
  
  CONCLUSIONS
  FKBP10 might be a novel drug target for IPF.
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Staab-Weijnitz
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Isis E
authors.initials: IE
authors.lastname: Fernandez
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Knüppel
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Maul
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heinzelmann
authors.affiliation: 2 Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Juan-Guardela
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hennen
authors.affiliation: 3 Thoraxchirurgisches Zentrum, Klinik für Allgemeine, Viszeral, Transplantations, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Preissler
authors.affiliation: 3 Thoraxchirurgisches Zentrum, Klinik für Allgemeine, Viszeral, Transplantations, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Winter
authors.affiliation: 4 Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität, Member of the German Center of Lung Research (DZL), Munich, Germany; and.
authors.forename: Claus
authors.initials: C
authors.lastname: Neurohr
authors.affiliation: 3 Thoraxchirurgisches Zentrum, Klinik für Allgemeine, Viszeral, Transplantations, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.|5 Asklepios Fachkliniken München-Gauting, Munich, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Hatz
authors.affiliation: 5 Asklepios Fachkliniken München-Gauting, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lindner
authors.affiliation: 4 Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität, Member of the German Center of Lung Research (DZL), Munich, Germany; and.|5 Asklepios Fachkliniken München-Gauting, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Behr
authors.affiliation: 2 Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
mesh_terms: D000328:Adult; D000818:Animals; D001761:Bleomycin; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D001761:Bleomycin; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human
keywords: FKBP65; collagen cross-linking; extracellular matrix; lung fibrosis; peptidyl-prolyl isomerase