The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice

Kohan, Martin; Muro, Andrés F.; Bader, Reem; Berkman, Neville

doi:10.1016/j.jaci.2010.10.021

Cited by 28 publications

(21 citation statements)

References 59 publications

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“…4b), and immunofluorescence (Fig. 4c) that FGF2 attenuates TGFβ-mediated expression of the myofibroblast-specific ED-A splice variant of fibronectin, an extracellular matrix protein that has been causally implicated in the myofibroblast activation and the development of tissue fibrosis [28–31]. We also demonstrated that culture in the presence of exogenous FGF2 was sufficient to attenuate the TGFβ-mediated expression of type I collagen, a major fibrillar collagen deposited in scar tissue.…”

Section: Resultsmentioning

confidence: 52%

FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts

Dolivo

Larson

Dominko

2017

Journal of Dermatological Science

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Background Previous human and animal studies have demonstrated the ability of exogenously administered basic fibroblast growth factor (FGF2) to act as an antifibrotic agent in the skin. Though the activity of FGF2 as an anti-scarring agent is well-established for fibrotic skin wounds, the mechanisms by which FGF2 exerts these actions are not entirely understood. Canonical FGF2 signaling proceeds in part via FGFR/MAPK pathways in human dermal fibroblasts, and FGF2 has been described to prevent or reverse the fibroblast-to-myofibroblast transition, which is driven by TGFβ signaling and understood to be an important step in the formation of a fibrotic scar in vivo. Thus, we set out to investigate the antagonistic effects of FGF2 on TGFβ signaling as well as the broader effects of MAPK inhibition on the TGFβ-mediated induction of myofibroblast gene expression. Objective To better understand the effects of FGF2 signaling pathways on myofibroblastic gene expression and cell phenotypes. Methods Human dermal fibroblasts were cultured in vitro in the presence of FGF2, TGFβ, and/or MAPK inhibitors, and the effects of these agents were investigated by molecular biology techniques including qRT-PCR, immunofluorescence, Western blot, and flow cytometry. Results FGF2 inhibited TGFβ-mediated fibroblast activation, resulting in more rapidly proliferating, spindle-shaped cells, compared to the more slowly proliferating, flatter TGFβ-treated cells. Treatment with FGF2 also attenuated TGFβ-mediated increase in expression of myofibroblast markers smooth muscle α-actin, calponin, transgelin, connective tissue growth factor, ED-A fibronectin, and collagen I. FGF2-mediated antagonism of the TGFβ-mediated fibroblast-to-myofibroblast transition was reversed by small molecule inhibition of ERK or JNK, and it was potentiated by inhibition of p38. MAPK inhibition was demonstrated to have qualitatively similar effects even in the absence of exogenous FGF2, and small molecule inhibition of p38 MAPK was sufficient to attenuate TGFβ-mediated fibroblast activation. Conclusions Inhibition of select MAPK signaling pathways can reverse or potentiate anti-fibrotic FGF2 effects on human dermal fibroblasts, as well as exert their effects independently of exogenous FGF2 supplementation.

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Section: Resultsmentioning

confidence: 52%

FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts

Dolivo

Larson

Dominko

2017

Journal of Dermatological Science

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“…Genetic studies in EDA null mice have documented a role for the EDA + -fibronectin in several models of tissue fibrosis. EDA + -fibronectin is required for the increase in matrix deposition and accumulation of myofibroblasts seen in subepithelial airway fibrosis (Kohan et al, 2011; Hirshoren et al, 2013). In the absence of EDA, mice were protected from cardiac fibrosis associated with chronic allograft rejection (Booth et al, 2012) and infarct (Arslan et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Myofibroblasts have a key role in wound healing where they mediate contractile forces required for wound closure (Powell et al, 1999). More recent studies in EDA null mice have documented a role for the EDA isoform of fibronectin in the generation of pathologic tissue fibrosis and inflammation (Booth et al, 2012; Kohan et al, 2011; Brem et al, 2000; Muro et al, 2008). EDA + - fibronectin also promotes the stromal reaction, a fibrotic condition seen in many cancers, which contributes to the creation of a microenvironment conducive for tumor progression (Xiang et al, 2012; Ou et al, 2013; Kelsh and McKeown-Longo, 2013).…”

Section: Introductionmentioning

confidence: 99%

The α4β1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts

et al. 2015

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Prompt deposition of fibronectin-rich extracellular matrix is a critical feature of normal development and the host-response to injury. Fibronectin isoforms that include the EDA and EDB domains are prominent in these fibronectin matrices. We now report using human dermal fibroblast cultures that the EDA domain of fibronectin or EDA-derived peptides modeled after the C-C’ loop promote stress fiber formation and myosin-light chain phosphorylation. These changes are accompanied by an increase in fibronectin synthesis and fibrillogenesis. These effects are blocked by pretreating cells with either siRNA or blocking antibody to the α4 integrin. Our data indicate that the interaction between the α4β1 integrin and the EDA domain of fibronectin helps to drive tissue fibrosis by promoting a contractile phenotype and an increase in fibronectin synthesis and deposition.

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“…Further work has shown that TGF‐β1, together with EDA cFN, induces the differentiation of fibroblasts into α‐SMA‐expressing myofibroblasts (36). The physiologic relevance of this mechanism has been highlighted in experimental models of lung fibrosis (34) and allergen‐induced airway fibrosis (37), in which EDA‐deficient mice were unable to generate α‐SMA‐expressing myofibroblasts at sites of injury, thereby preventing the development of tissue fibrosis. Similarly, EDA cFN is involved in the development of atherosclerosis, because EDA‐null mice develop significantly less atherosclerosis than wild‐type (WT) mice (12, 32).…”

Section: The Absence Of the Eda Domain Prevents Tissue Fibrosis: Fn‐tmentioning

confidence: 99%

Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models

2011

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SummaryThe extracellular matrix (ECM) is a highly dynamic network of proteins, glycoproteins, and proteoglycans. Numerous diseases result from mutation in genes coding for ECM proteins, but only recently it has been reported that mutations in the fibronectin (FN) gene were associated with a human disorder. FN is one of the main components of the ECM. It generates protein diversity through alternative splicing of a single pre-mRNA, having at least 20 different isoforms in humans. The precise function of these protein isoforms has remained obscure in most cases. Only in the recent few years, it was possible to shed light on the multiple roles of the alternatively spliced FN isoforms. This substantial progress was achieved basically with the knowledge derived from engineered mouse models bearing subtle mutations in specific FN domains. These data, together with a recent report associating mutations in the FN gene to a form of glomerulopathy, clearly show that mutations in constitutive exons or misregulation of alternatively spliced domains of the FN gene may have nonlethal pathological consequences. In this review, we focus on the pathological consequences of mutations in the FN gene, by connecting the function of alternatively spliced isoforms of fibronectin to human diseases.

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The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice

Cited by 28 publications

References 59 publications

FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts

FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts

The α4β1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts

Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models

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