FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Abstract

Rationale: 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).Objectives: To assess the expression and function of FKBP10 in IPF. Methods:We assessed FKBP10 expression in bleomycininduced 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-b 1 , 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 Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68 1 macrophages. Transforming growth factor-b 1 , 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 a-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.

Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing

“…We speculate that Fkbp10 silencing alters the quantity or crosslinking of the ECM and thereby alters mechanosensing. Consistent with our in vivo results, a prior in vitro study showed that inhibition of FKBP10 in primary human fibroblasts from pulmonary fibrosis patients attenuates expression of pro-fibrotic genes and decreases collagen secretion 36 . Thus, our findings expand the scope of Atp1a2 and Fkbp10 functions by demonstrating their novel roles in fibrogenesis in vivo.…”

Multiomic and quantitative label-free microscopy-based analysis ofex vivoculture and TGFbeta1 stimulation of human precision-cut lung slices

“…A curated data analysis of these proteins showed upregulation of prominent pro-fibrotic markers such as COL1A2, COL3A1, COL5A1, FBN-C and many others ( Figure 2B). Consistent with other studies many TGFß1 regulated profibrotic markers such as THBS1 31 , THBS2 32 , VCAN and TNC 33 , FKBP10 34 were upregulated as well. Furthermore, significantly regulated proteins were subjected to pathway analysis using Cytoscape ( Supplementary Figure2B).…”

Immune Mechanisms in Pulmonary Fibrosis

“…Immunoneutralization of IL-13 attenuated pulmonary fibrosis in bleomycin-induced pulmonary fibrosis (214) Moreover, pirfenidone decreased human lung fibroblast proliferation and differentiation into myofibroblasts by inhibiting TGF-β-induced phosphorylation of SMAD3 (221), while it has been shown ineffective in reducing collagen secretion in primary human lung fibroblasts in another study (222). Although, the initial report of the clinical trials was not concordant, CAPACITY-2, ASCEND, and a clinical trial performed in Japan demonstrated that pirfenidone slowed lung function decline and improved patient survival (223,224).…”