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Staab-Weijnitz, C.A. ; Fernandez, I.E. ; Knüppel, L. ; Maul, J. ; Heinzelmann, K. ; Juan-Guardela, B.M.* ; Hennen, E. ; Preissler, G.* ; Winter, H.* ; Neurohr, C.* ; Hatz, R.A.* ; Lindner, M.* ; Behr, J.* ; Kaminski, N.* ; Eickelberg, O.

FK506-binding protein 10 is a potential novel drug target for idiopathic pulmonary fibrosis.

Am. J. Respir. Crit. Care Med. 192, 455-467 (2015)
Verlagsversion Postprint DOI PMC
Open Access Green
RATIONALE: Increased abundance and stiffness of the extracellular matrix (ECM), in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which are described to lead to reduced ECM stiffness, e.g. in osteogenesis imperfecta. OBJECTIVES: To assess the expression and function of FKBP10 in IPF. METHODS: We assessed FKBP10 expression bleomycin-induced lung fibrosis (using qRT-PCR, Western Blot, and immunofluorescence), analysed microarray data from 99 IPF patients and 43 control subjects from a U.S. cohort, and performed Western Blot Analysis from 6 IPF patients 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 ER stress or TGF-β1, was analyzed by siRNA-mediated loss-of-function-experiments, qRT-PCR, 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 recently for IPF approved drugs nintedanib and pirfenidone. MEASUREMENTS AND MAIN RESULTS: FKBP10 expression was upregulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68+ macrophages. TGF-β1, but not ER stress, induced FKBP10 expression in phLF. The siRNA-mediated knockdown of FKBP10 attenuated expression of pro-fibrotic 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Fkbp65 ; Collagen Crosslinking ; Extracellular Matrix ; Lung Fibrosis ; Peptidyl-prolyl Isomerase; Endoplasmic-reticulum Stress; Extracellular-matrix; Osteogenesis Imperfecta; Developmental Regulation; Fibrogenic Activity; Acute Exacerbation; Bruck Syndrome; Collagen; Fkbp65; Lung
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 192, Heft: 4, Seiten: 455-467 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Verlagsort New York
Begutachtungsstatus