Surface proteome analysis identifies platelet derived growth factor receptor-alpha as a critical mediator of transforming growth factor-beta-induced collagen secretion

Heinzelmann, Katharina; Noskovičová, Nina; Merl-Pham, Juliane; Preißler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Hauck, Stefanie M.; Behr, Jürgen; Eickelberg, Oliver

doi:10.1016/j.biocel.2016.02.013

Cited by 13 publications

(18 citation statements)

References 54 publications

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“…In light of the time point studied (48 h after treatment start), this argues for a stronger and more sustained inhibition of the PI3K/Akt signaling pathway by nintedanib in our studies. Inhibition of PDGFR signaling, however, cannot explain all of our in vitro results, as a previous study from our lab(34) found that siRNA-mediated downregulation of PDGFR-α actually drastically increased levels of collagen V in primary human lung fibroblasts, which is in contrast to what we observe in presence of nintedanib.It is striking that many of the observed effects only translated to the protein level in presence of nintedanib, but not pirfenidone. For instance, both drugs inhibit TGF-β-induced COL1A1, COL3A1, and FN1 transcription whereas levels of collagen I protein, secreted collagen III, and fibronectin protein were only reduced by nintedanib in IPF fibroblasts(Figures 1, 2, E2).These results suggest that post-transcriptional regulation mechanisms are affected differently by the drugs and highlight the importance of analysis at the protein level in this context.…”

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confidence: 99%

“…While pirfenidone only showed these effects in the presence of exogenously added TGF-β1, nintedanib also affected basal levels of COL1A1 in IPF fibroblasts and also basal levels of another TGF-β target gene, PAI-1, in both IPF and donor fibroblasts ( Figures 1A and E3). As the platelet-derived growth factor (PDGF) receptor and fibroblast growth factor (FGF) receptor are known targets of the RTK inhibitor nintedanib, this might reflect inhibition of autocrine PDGF or FGF signaling, which has been shown to regulate collagen gene expression (5,33,34) via both ERK and PI3K/Akt signaling pathways (35). In agreement, Nevertheless, other studies have reported effects of pirfenidone on collagen I and/or fibronectin protein levels in normal phLF (20,26), alveolar epithelial cells (21), and nasal polyp fibroblasts (28).…”

Section: Nintedanib and Pirfenidone Inhibit Spontaneous Collagen I Fimentioning

confidence: 99%

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A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly

Knüppel¹,

Ishikawa

Aichler

et al. 2017

Am J Respir Cell Mol Biol

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121

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Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix, in particular, collagens. Two IPF therapeutics, nintedanib and pirfenidone, decelerate lung function decline, but their underlying mechanisms of action are poorly understood. In this study, we sought to analyze their effects on collagen synthesis and maturation at important regulatory levels. Primary human fibroblasts from patients with IPF and healthy donors were treated with nintedanib (0.01-1.0 μM) or pirfenidone (100-1,000 μM) in the absence or presence of transforming growth factor-β1. Effects on collagen, fibronectin, FKBP10, and HSP47 expression, and collagen I and III secretion, were analyzed by quantitative polymerase chain reaction and Western blot. The appearance of collagen fibrils was monitored by scanning electron microscopy, and the kinetics of collagen fibril assembly was assessed using a light-scattering approach. In IPF fibroblasts, nintedanib reduced the expression of collagen I and V, fibronectin, and FKBP10 and attenuated the secretion of collagen I and III. Pirfenidone also down-regulated collagen V but otherwise showed fewer and less pronounced effects. By and large, the effects were similar in donor fibroblasts. For both drugs, electron microscopy of IPF fibroblast cultures revealed fewer and thinner collagen fibrils compared with untreated controls. Finally, both drugs dose-dependently delayed fibril formation of purified collagen I. In summary, both drugs act on important regulatory levels in collagen synthesis and processing. Nintedanib was more effective in down-regulating profibrotic gene expression and collagen secretion. Importantly, both drugs inhibited collagen I fibril formation and caused a reduction in and an altered appearance of collagen fibril bundles, representing a completely novel mechanism of action for both drugs.

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confidence: 99%

Section: Nintedanib and Pirfenidone Inhibit Spontaneous Collagen I Fimentioning

confidence: 99%

A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly

Knüppel¹,

Ishikawa

Aichler

et al. 2017

Am J Respir Cell Mol Biol

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121

View full text Add to dashboard Cite

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“…A possible mechanism underlying the TGF-β-driven alveolar pathology is indicated by in vitro findings that show a reduction of PDGF expression by TGF β in adult pulmonary mesenchymal cells [ 76 ]. Heinzelmann et al furthermore demonstrate a negative correlation between TGF-β stimulation and PDGF-Rα expression in adult human lung fibroblasts [ 77 ]. Translating these findings into the developing human lung, recent studies performed by Popova et al display a downregulation in PDGF-Rα expression upon TGF-β treatment in lung mesenchymal-like cells (MSCs) obtained from BPD patients [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease

Oak

Hilgendorff

2017

Mol Cell Pediatr

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The development of neonatal chronic lung disease (nCLD), i.e., bronchopulmonary dysplasia (BPD) in preterm infants, significantly determines long-term outcome in this patient population. Risk factors include mechanical ventilation and oxygen toxicity impacting on the immature lung resulting in impaired alveolarization and vascularization. Disease development is characterized by inflammation, extracellular matrix remodeling, and apoptosis, closely intertwined with the dysregulation of growth factor signaling. This review focuses on the causes and consequences of altered signaling in central pathways like transforming growth factor (TGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) driving these above indicated processes, i.e., inflammation, matrix remodeling, and vascular development. We emphasize the shared and distinct role of these pathways as well as their interconnection in disease initiation and progression, generating important knowledge for the development of future treatment strategies.

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“…the CC chemokine ligand CCL24, surfactant protein A2, and transcriptional factors NF-κB, peroxisome proliferator-activated receptor-γ and c-Myc [20][21][22]. Recently, it was reported from proteomics analysis of fibroblast surface fractions that platelet-derived growth factor receptor (PDGFR)-α expression was altered by pro-fibrotic TGF-β in lung fibroblasts from IPF patients [23]. The authors suggest a potential cross-talk between two critical signalling pathways in fibrosis, i.e.…”

Section: Proteomicsmentioning

confidence: 99%

“…The authors suggest a potential cross-talk between two critical signalling pathways in fibrosis, i.e. TGF-β/PDGFR-α, which affects myofibroblast differentiation in the context of IPF [23], currently insufficiently targeted by approved therapies.…”

Section: Proteomicsmentioning

confidence: 99%

Systems medicine advances in interstitial lung disease

2017

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Fibrotic lung diseases involve subject-environment interactions, together with dysregulated homeostatic processes, impaired DNA repair and distorted immune functions. Systems medicine-based approaches are used to analyse diseases in a holistic manner, by integrating systems biology platforms along with clinical parameters, for the purpose of understanding disease origin, progression, exacerbation and remission.Interstitial lung diseases (ILDs) refer to a heterogeneous group of complex fibrotic diseases. The increase of systems medicine-based approaches in the understanding of ILDs provides exceptional advantages by improving diagnostics, unravelling phenotypical differences, and stratifying patient populations by predictable outcomes and personalised treatments. This review discusses the state-of-the-art contributions of systems medicine-based approaches in ILDs over the past 5 years.

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Surface proteome analysis identifies platelet derived growth factor receptor-alpha as a critical mediator of transforming growth factor-beta-induced collagen secretion

Cited by 13 publications

References 54 publications

A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly

A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly

The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease

Systems medicine advances in interstitial lung disease

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