• Claudia A Staab-Weijnitz, Isis E Fernandez, Larissa Knüppel, Julia Maul, Katharina Heinzelmann, Brenda M Juan-Guardela, Elisabeth Hennen, Gerhard Preissler, Hauke Winter, Claus Neurohr, Rudolf Hatz, Michael Lindner, Jürgen Behr, Naftali Kaminski, and Oliver Eickelberg.
• 1 Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
• Am. J. Respir. Crit. Care Med. 2015 Aug 15;192(4):455-67.

RationaleIncreased 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).ObjectivesTo assess the expression and function of FKBP10 in IPF.MethodsWe 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.Measurements And Main ResultsFKBP10 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.ConclusionsFKBP10 might be a novel drug target for IPF.

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