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Cited by 153Systemic Sclerosis and Related DiseasesDupuytren's Contracture and TreatmentsPulmonary Hypertension Research and Treatments

Unraveling SSc Pathophysiology; The Myofibroblast

Open access
van Caam, Arjan, Vonk, Madelon, van den Hoogen, Frank, van Lent, Peter, van der Kraan, Peter·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.02452PMC PMC6242950
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Abstract

Systemic sclerosis (SSc) is a severe auto-immune disease, characterized by vasculopathy and fibrosis of connective tissues. SSc has a high morbidity and mortality and unfortunately no disease modifying therapy is currently available. A key cell in the pathophysiology of SSc is the myofibroblast. Myofibroblasts are fibroblasts with contractile properties that produce a large amount of pro-fibrotic extracellular matrix molecules such as collagen type I. In this narrative review we will discuss the presence, formation, and role of myofibroblasts in SSc, and how these processes are stimulated and mediated by cells of the (innate) immune system such as mast cells and T helper 2 lymphocytes. Furthermore, current novel therapeutic approaches to target myofibroblasts will be highlighted for future perspective.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that myofibroblasts are central to systemic sclerosis (SSc) pathophysiology through increased formation, decreased apoptosis, and increased activity, driven by TGFβ, mechanotransduction, and immune mediators. It reviews candidate therapies targeting these pathways, noting mixed clinical results and several phase 3 trials underway.

Key findings

  • SSc is described as rare but severe, with an estimated incidence of ~13 people per 1 million per year and prevalence of ~200 per 1 million; all-cause standardized mortality ratio averages 2.7, and estimated loss of life expectancy exceeds 15 years.
  • Myofibroblasts are present in affected SSc skin, lungs, esophagus, and gastric wall; their presence correlates with skin fibrosis parameters more significantly than inflammation, and in late-stage fibrotic atrophic SSc skin they can no longer be detected.
  • Myofibroblast accumulation in SSc is attributed to decreased apoptosis (e.g., lower pro-apoptotic BAX, increased c-Abl, stiffness/ROCK/BCL2-XL signaling, increased PI3K/AKT, and miRNA21) and increased formation via TGFβ, PDGF, Wnt, IL-6/STAT3, mechanosensing, and FN1 EDA, with possible origins including pericytes, fibrocytes, adipocytes, EMT, and EndoMT.
  • Immune cells shape myofibroblast function: mast cells, neutrophils, macrophages, Th2, and Th17 cells are largely pro-fibrotic, while NK cells and Th1 cells can be anti-fibrotic; therapeutic trials show mixed results, e.g., abatacept produced ≥30% skin score improvement in 5/7 (71%) abatacept-treated vs 1/3 (33%) placebo-treated patients, while tocilizumab did not significantly reduce skin thickening in its phase 2 trial but showed skin score improvement and FVC stabilization in the open-label extension.

Methods

  • Narrative review; no systematic search strategy, primary data collection, or meta-analysis is reported.
  • Synthesizes literature on myofibroblast biology, presence in SSc, apoptosis, formation pathways, cellular origins, immune interactions, and therapeutic targeting.
  • Main analysis is qualitative narrative synthesis, supported by a cytokine-effect table and tables of completed and ongoing clinical trials.

Limitations

  • The paper does not state limitations.
  • Evident from the text: as a narrative review, it lacks a systematic search and quantitative synthesis, so selection and interpretation bias cannot be excluded.
  • Evident from the text: many mechanistic conclusions rely on in vitro, murine, or cited studies, and the clinical trial evidence summarized is heterogeneous, often small, and includes negative or mixed results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fimmu.2018.02452

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 227 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Myofibroblasts produce and/or activate various autocrine and paracrine mediators including VEGF, endothelin 1, CTGF, TGFβ, IL-1, IL-6, IL-8, and MCP-1.

    “Myofibroblasts also secrete and/or activate various autocrine and paracrine mediators to facilitate wound healing.”
    • Also stated in: § On the myofibroblast and its biological function · plain
      “Most notably, they produce interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), and monocyte chemoattractive protein 1 (MCP-1) (13).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Kendall, 2014, Fibroblasts in fibrosis: novel roles and mediators, Front Pharmacol. source

      Not checked in the free run.

    • cites [14] Lagares, 2012, Adenoviral gene transfer of endothelin-1 in the lung induces pulmonary fibrosis through the activation of focal adhesion kinase, Am J Res Cell Mol Biol. source

      Not checked in the free run.

    • cites [15] Lagares, 2010, Endothelin 1 contributes to the effect of transforming growth factor beta1 on wound repair and skin fibrosis, Arthritis Rheum. source

      Not checked in the free run.

  • Premisecitation

    Myofibroblasts express crosslinking enzymes such as transglutaminase 2, LOX, and PLOD2 that strengthen ECM by increasing collagen crosslinking.

    “myofibroblasts express several protein and collagen crosslinking enzymes such as protein-glutamine gamma-glutamyltransferase 2 (=transglutaminase 2), protein-lysine 6-oxidase (LOX), and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Klingberg, 2013, The myofibroblast matrix: implications for tissue repair and fibrosis, J Pathol. source

      Not checked in the free run.

  • Premisecitation

    Myofibroblasts strongly connect physically to their environment via integrin-mediated focal adhesions and cadherin-mediated adherens junctions.

    “via integrin-mediated focal adhesions and cadherin-mediated adherens junctions their actin cytoskeleton is strongly anchored to their surrounding ECM and neighboring cells, respectively (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Hinz, 2003, Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts, Mol Biol Cell source

      Not checked in the free run.

  • Premisecitation

    Silencing c-ABL enhances apoptosis in both healthy and SSc skin fibroblasts by increasing the BAX/BCL2 ratio toward pro-apoptotic BAX.

    “Silencing of c-ABL enhances apoptosis in both healthy and SSc skin fibroblasts by increasing the BAX/BCL2 ratio toward pro-apoptotic BAX (34).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Karimizadeh, 2015, c-Abl silencing reduced the inhibitory effects of TGF-beta1 on apoptosis in systemic sclerosis dermal fibroblasts, Mol Cell Biochem. source

      Not checked in the free run.

  • Premisecitation

    Myofibroblasts can originate via differentiation of fibroblasts toward myofibroblasts, a process facilitated by growth factors such as TGFβ, Wnts, damage associated molecular patterns such as fibronectin cloths, and tissue stiffness.

    “Myofibroblasts can originate in several ways, including the differentiation of fibroblasts toward myofibroblasts. This process is key in normal wound healing and facilitated by growth factors such as TGFβ, Wnts, damage associated molecular patterns such as fibronectin cloths, and tissue stiffness; the stiffer the matrix the more prone fibroblasts are to become myofibroblasts (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Hinz, 2009, Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis, Curr Rheumatol Rep. source

      Not checked in the free run.

  • May combine two claims. 79
  • Classified as probably not a substantial claim. 2

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    Premisecitation

    Myofibroblasts are key in open wound closure and facilitate wound healing.

    “Myofibroblasts facilitate wound healing in several ways (Figure 1);”
    • Also stated in: § On the myofibroblast and its biological function · boosted
      “This contraction decreases wound size and is crucial for open wound healing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Gabbiani, 1972, Granulation tissue as a contractile organ, J Exp Med. source

      Not checked in the free run.

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    Premisecitation

    Myofibroblasts are fibroblasts with contractile properties that produce large amounts of pro-fibrotic extracellular matrix molecules such as collagen type I.

    “Myofibroblasts are fibroblasts with contractile properties that produce a large amount of pro-fibrotic extracellular matrix molecules such as collagen type I.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Gabbiani, 1971, Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction, Experientia source

      Not checked in the free run.

    • cites [9] Gabbiani, 1972, Granulation tissue as a contractile organ, J Exp Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myofibroblasts are contractile; their stress fibers consist of alpha smooth muscle actin (αSMA) and non-muscle myosin type II and contract in actin-myosin fashion.

    “Their microfilaments (also known as stress fibers) consist of alpha smooth muscle actin (αSMA) and non-muscle myosin type II (10) and can contract in typical actin-myosin fashion, albeit rather slowly compared to muscle actin myosin filaments.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Bond, 2011, Temporal spatial expression and function of non-muscle myosin II isoforms IIA and IIB in scar remodeling, Laborat Invest. source

      Not checked in the free run.

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    Premisecitation

    TGFβ is produced and potently activated by myofibroblasts and is strongly pro-fibrotic, stimulating myofibroblast formation and activity.

    “A key growth factor which is produced (13) and potently activated by myofibroblasts is transforming growth factor β (TGFβ) (16). This polypeptide growth factor is strongly pro-fibrotic and stimulates myofibroblast formation and activity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Kendall, 2014, Fibroblasts in fibrosis: novel roles and mediators, Front Pharmacol. source

      Not checked in the free run.

    • cites [16] Wipff, 2007, Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix, J Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    TGFβ directly induces extracellular matrix production and αSMA expression in fibroblasts.

    “To begin, a key growth factor for myofibroblast formation is TGFβ; this growth factor directly induces extracellular matrix production and αSMA expression in fibroblasts.”
    Quote in the paperSubstantial claim

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    Premisecitation

    TGFβ lowers expression of SMPD1; reduction in SMPD1 enhances pro-survival AKT signaling and reduces Fas-dependent apoptosis.

    “Furthermore, TGFβ signaling also lowers expression of acid sphingomyelinase (SMPD1) (39). This enzyme induces the activation of protein phosphatase 2 (PP2A), i.e., an inhibitor of AKT signaling, and a reduction in SMPD1 thus enhances pro-survival AKT signaling. Additionaly, SMPD1 facilitates Fas-dependent apoptosis via its product; i.e., the lipid ceramide, which helps cluster Fas at the cell mem”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Samuel, 2012, Acid sphingomyelinase deficiency contributes to resistance of scleroderma fibroblasts to Fas-mediated apoptosis, J Dermatol Sci. source

      Not checked in the free run.

    • cites [40] Smith, 2008, The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases, FASEB J. source

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    Premisecitation

    TGFβ activity is increased in skin of SSc patients, as is expression of its activating integrin αVβ5.

    “TGFβ activity is increased in skin of SSc patients, just as expression of its activating integrin αVβ5 (43, 44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Asano, 2005, Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts, Arthritis Rheum. source

      Not checked in the free run.

    • cites [44] Asano, 2006, Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblasts, Am J Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In SSc, myofibroblast presence is unwanted and attributed to a lowered susceptibility of myofibroblasts to undergo apoptosis and to increased formation.

    “In contrast, in SSc their presence is unwanted and attributed to a lowered susceptibility of myofibroblasts to undergo apoptosis and to increased formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In SSc skin, expression of miRNA21 is increased, and miRNA21 targets and degrades pro-apoptotic BAX mRNA and targets PTEN, lowering cellular sensitivity to apoptosis.

    “In SSc skin, expression of miRNA21 is increased, and this miRNA targets and degrades pro-apoptotic BAX mRNA (41). Additionally, miRNA21 targets phosphatase and tensin homolog (PTEN), which is an inhibitor of AKT signaling, as this phosphatase lowers intracellular PIP3 levels, the activator of AKT signaling (38).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Jafarinejad-Farsangi, 2016, Inhibition of MicroRNA-21 induces apoptosis in dermal fibroblasts of patients with systemic sclerosis, Int J Dermatol. source

      Not checked in the free run.

    • cites [38] Liu, 2016, TGF-beta1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21, Sci Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In lungs of SSc patients, myofibroblasts in the interstitial space can be observed early during the fibrotic process, and with progression of interstitial lung disease they can also be observed in bronchoalveolar lavage liquid.

    “In lungs of SSc patients, the presence of myofibroblasts in the interstitial space can already be observed early during the fibrotic process (24), and with progression of interstitial lung disease they can ultimately also be observed in bronchoalveolar lavage liquid of SSc patients (25).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Beon, 2004, Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis, Clin Exp Rheumatol.

      Not checked in the free run.

    • cites [25] Ludwicka, 1992, Growth and characterization of fibroblasts obtained from bronchoalveolar lavage of patients with scleroderma, J Rheumatol.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGFβ signaling is increased in skin of SSc patients, and TGFβ induces AKT signaling in dermal fibroblasts to lower myofibroblasts' sensitivity for Fas-mediated apoptosis.

    “TGFβ signaling is increased in skin of SSc patients, and TGFβ has been demonstrated to induce AKT signaling in dermal fibroblasts to lower myofibroblasts' sensitivity for Fas-mediated apoptosis (34, 37, 38).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [34] Karimizadeh, 2015, c-Abl silencing reduced the inhibitory effects of TGF-beta1 on apoptosis in systemic sclerosis dermal fibroblasts, Mol Cell Biochem. source

      Not checked in the free run.

    • cites [37] Jelaska, 2000, Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis, Arthritis Rheum. source

      Not checked in the free run.

    • cites [38] Liu, 2016, TGF-beta1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21, Sci Rep. source

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  • May combine two claims.

    Premisecitation

    Fibroblasts of SSc patients near lesional areas in skin, esophagus, and lungs contain alpha smooth muscle actin and are thus myofibroblasts.

    “In 1990 it was confirmed using immunohistochemistry that fibroblasts of SSc patients near lesional areas in skin, esophagus, and lungs contain alpha smooth muscle actin (20) and are thus myofibroblasts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Sappino, 1990, Smooth muscle differentiation in scleroderma fibroblastic cells, Am J Pathol.

      Not checked in the free run.

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    Premisecitation

    Increased extracellular matrix stiffness is an important survival signal for myofibroblasts; via mechanosensing it activates Rho and ROCK, increasing BCL2-XL expression.

    “This increased stiffness is an important survival signal for myofibroblasts; via mechanosensing such stiffness results in intracellular activation of Rho and Rho-associated kinase (ROCK) whose activity increases BCL2-XL expression (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Lagares, 2017, Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis, Sci Trans Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myofibroblasts can be detected in the esophagus and gastric wall of SSc patients with severe fibrosis, where their presence results in loss of muscle function and gastro-oesophageal reflux disease.

    “Another location where myofibroblasts can be detected in SSc is in the esophagus and gastric wall of patients with severe fibrosis (26). Here, myofibroblast presence results in loss of muscle function, making these tissues unable to contract. As a consequence, gastric acid can flow into the esophagus, causing gastro-oesophageal reflux disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Manetti, 2007, Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients, Arthritis Rheum. source

      Not checked in the free run.

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    Premisecitation

    Pharmacological inhibition of BCL2-XL can induce targeted BIM-mediated apoptosis in myofibroblasts and revert established murine fibrosis.

    “Recently, it has been shown that pharmacological inhibition of BCL2-XL can mimic this process and induce targeted BIM-mediated apoptosis in myofibroblasts and even revert established (murine) fibrosis (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Lagares, 2017, Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis, Sci Trans Med. source

      Not checked in the free run.

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    Premisecitation

    Overexpression of SMAD3 enhances, whereas knockdown inhibits αSMA and extracellular matrix production in fibroblasts; fibroblast-specific deletion of SMAD3 reduces αSMA production and myofibroblast phenotype.

    “Overexpression of SMAD3 enhances, whereas knockdown inhibits αSMA and extracellular matrix production in fibroblasts (45–48). Furthermore, fibroblast-specific deletion of SMAD3 reduces αSMA production and myofibroblast phenotype (49–52), for example, loss of SMAD3 lowers the number of activated myofibroblasts in cardiac fibrosis in vivo and reduces extracellular matrix production by myofibroblasts”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [45] Hu, 2003, Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression, Am J Respir Cell Mol Biol. source

      Not checked in the free run.

    • cites [46] Gu, 2007, Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation, Acta Pharmacol Sin. source

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    • cites [47] Khalil, 2017, Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis, J Clin Invest. source

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    • cites [48] Dobaczewski, 2010, Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction, Circul Res. source

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    • cites [49] Kulkarni, 2011, PPAR-gamma ligands repress TGFbeta-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis, PLoS ONE source

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    • cites [50] Abdalla, 2013, Akt1 mediates alpha-smooth muscle actin expression and myofibroblast differentiation via myocardin and serum response factor, J Biol Chem. source

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    • cites [51] Lu, 2010, Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production, Am J Respir Cell Mol Biol. source

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    • cites [52] Hsu, 2017, Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis, Sci Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibroblasts obtained from SSc skin have a pro-fibrotic phenotype and produce more collagens than control fibroblasts.

    “Already in 1972 it was identified that fibroblasts obtained from SSc skin have a pro-fibrotic phenotype and produce more collagens than control fibroblasts (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Leroy, 1972, Connective tissue synthesis by scleroderma skin fibroblasts in cell culture, J Exp Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stiffness-induced BCL2-XL expression is needed to counteract pro-apoptotic BIM, which accumulates in myofibroblasts exposed to a stiff matrix and primes them for apoptosis.

    “Importantly, this increased, stiffness-induced, BCL2-XL expression is needed to counteract the function of the pro-apoptotic protein BIM (36). BIM is an activator of BAX and accumulates in myofibroblasts exposed to a stiff matrix. This accumulation primes the cells to undergo apoptosis (36), and only the continued presence of BCL2-XL prevents this.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Lagares, 2017, Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis, Sci Trans Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In both bleomycin-induced skin and lung fibrosis in mice, knockout or pharmacological inhibition of STAT3 ameliorates fibrosis, and STAT3 is downstream of TGFβ signaling.

    “Importantly, in both bleomycin induced skin and lung fibrosis in mice, knockout or pharmacological inhibition of STAT3 ameliorates fibrosis (83) (81). Furthermore, in both models, STAT3 was shown to be downstream of TGFβ signaling, as inhibition of STAT3 prevented TGFβ-induced myofibroblasts formation (81, 83).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Pedroza, 2016, STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation, FASEB J. source

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    • cites [81] Chakraborty, 2017, Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis, Nat Commun. source

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    Premisecitation

    TGFβ signaling via p38 MAPK lowers DKK1 expression, an inhibitor of canonical Wnt signaling via β-catenin; SSc skin and fibroblasts show decreased DKK1, increased β-catenin accumulation, and increased Wnt-related gene expression.

    “TGFβ signaling via p38 MAPK lowers dickkopf-1 (DKK1) expression (62), which is an inhibitor of canonical Wnt signaling via β-catenin. In skin and fibroblasts of SSc patients, decreased DKK1 expression is observed (62), together with increased β-catenin accumulation (63), and increased expression of Wnt signaling-related genes (62, 64).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Akhmetshina, 2012, Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis, Nat Commun. source

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    • cites [63] Beyer, 2012, Beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis, Ann Rheum Dis. source

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    • cites [64] Wei, 2012, Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells, Arthritis Rheum. source

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    Premisecitation

    In SSc skin, STAT3 signaling is activated and regulates collagen type I expression in SSc skin fibroblasts; in lungs of SSc patients no enhanced STAT3 activation is observed.

    “In SSc skin, STAT3 signaling is activated (81) resulting in pro-fibrotic gene expression in fibroblasts; for example, STAT3 regulates collagen type I expression in SSc skin fibroblasts (82). However, of note, in lungs of SSc patients no enhanced STAT3 activation can be observed (82).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Chakraborty, 2017, Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis, Nat Commun. source

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    • cites [82] Papaioannou, 2018, STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation, Mol Biol Cell source

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    Premisecitation

    p38 MAPK inhibitors lower TGFβ-induced collagen type I and αSMA production and prevent TGFβ-induced AKT signaling.

    “The use of p38 MAPK inhibitors also lowers TGFβ-induced collagen type I and αSMA production and prevents TGFβ-induced AKT signaling (53–55).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53] Meyer-Ter-Vehn, 2006, p38 inhibitors prevent TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts, Invest Ophthalmol Vis Sci. source

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    • cites [54] Sanders, 2015, SMAD-independent down-regulation of caveolin-1 by TGF-beta: effects on proliferation and survival of myofibroblasts, PLoS ONE source

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    • cites [55] Horowitz, 2004, Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor, J Biol Chem. source

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  • May combine two claims.

    Premisecitation

    Wnt signaling can induce autocrine TGFβ signaling, and overexpression of DKK1 protects mice against TGFβ-receptor mediated skin fibrosis, indicating both pathways are interdependent.

    “Notably, Wnt signaling can induce autocrine TGFβ signaling (64) and overexpression of DKK1 protects mice even against TGFβ-receptor mediated skin fibrosis, indicating that both pathways are closely interwoven and interdependent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Wei, 2012, Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SSc skin fibroblasts, TGFβ makes fibroblasts more sensitive to PDGF via induction of PDGFR; PDGF induces extracellular matrix production and proliferation via PI3K/AKT, p38 MAPK, c-ABL, and FAK pathways.

    “In SSc skin fibroblasts, TGFβ makes fibroblasts more sensitive to anabolic stimulation with platelet derived growth factor (PDGF), via induction of its receptor (PDGFR) (59). This growth factor induces extracellular matrix production and proliferation via the activation of PI3K/AKT, p38 MAPK, c-ABL, and focal adhesion kinase (FAK) pathways.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Yamakage, 1992, Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts, J Exp Med. source

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    Interpretationcitation

    Pericyte to myofibroblast transition is observed in lung, liver, and kidney fibrosis, indicating that it is a common aspect of many fibrotic disorders.

    “In addition, this transition is also observed in lung, liver, and kidney fibrosis (85), indicating that pericyte to myofibroblast transition is a common aspect of many fibrotic disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Greenhalgh, 2013, Origins of fibrosis: pericytes take centre stage, F1000Prime Rep. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    YAP/TAZ and TGFβ activity can result in a feed forward loop in which tissue stiffness results in tissue stiffness-enhancing activity, explaining continued fibrosis in absence of an exogenous stimulus.

    “Both YAP/TAZ and TGFβ activity can thus result in a feed forward loop in which tissue stiffness results in tissue stiffness-enhancing activity. Such a mechanism can explain continued fibrosis in absence of a exogenous stimulus.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Myofibroblasts can originate from various cell types, including fibroblasts, adipocytes, monocytes/fibrocytes, pericytes, endothelial cells, and epithelial cells.

    “Myofibroblasts can originate from various cell types, including fibroblasts, adipocytes, monocytes/fibrocytes, pericytes, endothelial cells, and epithelial cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TGFβ can induce expression of FN1 EDA in (myo)fibroblasts; FN1 EDA is normally not expressed in healthy tissues but is induced during wound healing, and its presence is a prerequisite for TGFβ-mediated myofibroblast formation.

    “Apart from the abovementioned effects, TGFβ can induce the expression of fibronectin 1 extra domain A (FN1 EDA) in (myo) fibroblasts. FN1 EDA is a splice variant of fibronectin which contains the so-called EDA domain. Normally, FN1 EDA is not expressed in healthy tissues but its expression is induced during wound healing (65) Fibroblasts can detect FN1 EDA via membrane bound receptors such as α4”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [65] White, 2011, Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse models, IUBMB Life source

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    • cites [66] Serini, 1998, The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1, J Cell Biol. source

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    • cites [67] Muro, 2008, An essential role for fibronectin extra type III domain A in pulmonary fibrosis, Am J Respir Critic Care Med. source

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    Premisecitation

    Transgenic overexpression of Fra-2 results in increased dermal thickness and myofibroblast formation and is a mouse model for SSc.

    “This transcription factor has been identified as an important regulator of extracellular matrix production in skin fibroblasts; transgenic overexpression of Fra-2 results in increased dermal thickness and myofibroblast formation and is a mouse model for SSc (101), whereas knockdown of Fra-2 reduces both TGFβ- and PDGF-induced collagen production in primary skin fibroblasts of SSc patients (102).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Maurer, 2013, The Fra-2 transgenic mouse model of systemic sclerosis, Vascul Pharmacol. source

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    Premisecitation

    EndoMT can be identified using immunohistochemistry by observing endothelial cells with both endothelial markers (CD31, VE-cadherin) and myofibroblast markers (αSMA), and has been observed in skin and in lungs of SSc patients.

    “EndoMT can be identified using immunohistochemistry by observing endothelial cells with both endothelial (cluster of differentiation (CD31, and VE-cadherin) and myofibroblast markers (αSMA), and has been observed in skin and in lungs of SSc patients (92, 93).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Manetti, 2017, Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

    • cites [93] Mendoza, 2015, Endothelial cells expressing endothelial and mesenchymal cell gene products in Systemic Sclerosis-associated interstitial lung disease lung tissues, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking FIZZ1 retain more fat and develop less fibrosis in response to bleomycin skin injury.

    “Furthermore, mice lacking FIZZ1 retain more fat and develop less fibrosis in response to bleomycin skin injury (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Martins, 2015, FIZZ1-induced myofibroblast transdifferentiation from adipocytes and its potential role in dermal fibrosis and lipoatrophy, Am J Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SSc skin, expression of the key EMT inducing transcription factor SNAI1 can be observed in keratinocytes, but not loss of their epithelial E-Cadherin marker.

    “In SSc skin, expression of the key EMT inducing transcription factor SNAI1 can be observed in keratinocytes, but not loss of their epithelial E-Cadherin marker (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Nikitorowicz-Buniak, 2015, Partially evoked epithelial-mesenchymal transition (EMT) is associated with increased TGFbeta signaling within lesional scleroderma skin, PLoS ONE source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    JMJD3 removes the H3K27me3 mark from histones, and this mark can repress expression of pro-fibrotic genes such as collagen type I in fibroblasts.

    “This histone demethylase removes the so-called H3K27me3 mark from histones, and this mark can repress expression of pro-fibrotic genes such as collagen type I in fibroblasts (100).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Kramer, 2013, Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In the murine bleomycin model of skin fibrosis, loss of fat tissue precedes fibrosis, indicating that adipocyte to myofibroblast transition can underlie the fibrotic process.

    “Importantly, in this model of skin fibrosis the loss of fat tissue precedes fibrosis (88) indicating that this process can underlie the fibrotic process.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Marangoni, 2015, Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors, Arthritis Rheumatol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both EMT and EndoMT can be observed in SSc.

    “Both processes can be observed in SSc.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Manetti, 2017, Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

    • cites [93] Mendoza, 2015, Endothelial cells expressing endothelial and mesenchymal cell gene products in Systemic Sclerosis-associated interstitial lung disease lung tissues, Arthritis Rheum. source

      Not checked in the free run.

    • cites [95] Kim, 2006, Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix, Proc Natl Acad Sci USA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, (myo)fibroblasts obtained from SSc patients produce more extracellular matrix molecules such as collagen type I than those of healthy controls, and their migratory and contractile properties are also increased.

    “Furthermore, in vitro, (myo)fibroblasts obtained from SSc patients produce more extracellular matrix molecules such as collagen type I than those of healthy controls, and their migratory and contractile properties are also increased (19, 98).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Leroy, 1972, Connective tissue synthesis by scleroderma skin fibroblasts in cell culture, J Exp Med. source

      Not checked in the free run.

    • cites [98] Denton, 2018, Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, FIZZ1 suppresses adipogenesis and stimulates myofibroblast differentiation via Notch1 signaling.

    “In vitro, FIZZ1 suppresses adipogenesis and stimulates myofibroblast differentiation via Notch1 signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Wei, 2011, Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In EMT and EndoMT, epithelial and endothelial cells lose their phenotype and become myofibroblasts.

    “In both processes, respectively epithelial and endothelial cells lose their phenotype and become myofibroblasts.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Manetti, 2017, Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

    • cites [93] Mendoza, 2015, Endothelial cells expressing endothelial and mesenchymal cell gene products in Systemic Sclerosis-associated interstitial lung disease lung tissues, Arthritis Rheum. source

      Not checked in the free run.

    • cites [95] Kim, 2006, Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix, Proc Natl Acad Sci USA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological inhibition of H3K27 trimethylation induces skin fibrosis and aggravates pathology in bleomycin induced skin fibrosis.

    “Furthermore, pharmacological inhibition of H3K27 trimethylation induces skin fibrosis and aggravates pathology in bleomcyin induced skin fibrosis (100).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Kramer, 2013, Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two important sources of myofibroblasts in SSc are epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndoMT).

    “Finally, two important sources of myofibroblasts in SSc are epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndoMT).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Manetti, 2017, Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

    • cites [93] Mendoza, 2015, Endothelial cells expressing endothelial and mesenchymal cell gene products in Systemic Sclerosis-associated interstitial lung disease lung tissues, Arthritis Rheum. source

      Not checked in the free run.

    • cites [95] Kim, 2006, Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix, Proc Natl Acad Sci USA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myofibroblasts produce VEGF and can express angiopoietin 1 and 2, both of which stimulate the formation of new blood vessels.

    “Furthermore, myofibroblasts also produce VEGF (154), e.g., during wound healing, and can also express angiopoietin 1 and 2, both of which stimulate the formation of new blood vessels (155).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [154] Distler, 2004, Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis, Circul Res. source

      Not checked in the free run.

    • cites [155] Staton, 2010, Angiopoietin-1, angiopoietin-2 and Tie-2 receptor expression in human dermal wound repair and scarring, Br J Dermatol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFNγ inhibits collagen synthesis, sensitizes dermal fibroblasts to Fas-mediated apoptosis, and inhibits IL-4 effects.

    “For example, interferon γ (IFNγ) inhibits collagen synthesis, sensitizes dermal fibroblast to Fas-mediated apoptosis (125, 126) and inhibits IL-4 effects (125).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [125] Serpier, 1997, Antagonistic effects of interferon-gamma and interleukin-4 on fibroblast cultures, J Invest Dermatol. source

      Not checked in the free run.

    • cites [126] Rosenbloom, 1986, Inhibition of excessive scleroderma fibroblast collagen production by recombinant gamma-interferon, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the gastro-intestinal tract, myofibroblast-induced fibrosis negatively affects motility, digestion, absorption, and excretion.

    “In the gastro-intestinal tract, myofibroblast-induced fibrosis negatively affect motility, digestion, absorption, and excretion (153).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Forbes, 2009, Gastrointestinal complications: the most frequent internal complications of systemic sclerosis, Rheumatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF2 can inhibit TGFβ-mediated myofibroblast formation but can also increase myofibroblast proliferation.

    “The role of basic fibroblast growth factor (FGF2) is less clear, as it can inhibit TGFβ-mediated myofibroblast formation (140), but can also increase myofibroblast proliferation (151).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Dolivo, 2017, FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts, J Dermatol Sci. source

      Not checked in the free run.

    • cites [151] Perl, 2009, FGF signaling is required for myofibroblast differentiation during alveolar regeneration, Am J Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both IL-1 and IL-6 can participate in the differentiation of monocytes toward macrophages and play a role in the differentiation of naive T-cells toward an effector subtype.

    “Furthermore, both factors can participate in the differentiation of monocytes toward macrophages and play a role in the differentiation of naive T-cells toward an effector subtype (156).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Arango Duque, 2014, Macrophage cytokines: involvement in immunity and infectious diseases, Front Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In skin, excessive matrix deposition increases stiffness, increases hardness, and leads to loss of cutaneous tissues like fat tissue, sweat glands, hair follicles, and sebaceous glands.

    “In skin excessive matrix deposition increases stiffness, increases hardness, and leads to loss of cutaneous tissues like, fat tissue, sweat glands, hair follicles, and sebaceous glands (152).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Krieg, 2009, Skin disease: a cardinal feature of systemic sclerosis, Rheumatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of serotonin on extracellular matrix production runs via the 5H-T2b receptor; inhibition of this receptor with terguride decreases collagen and fibronectin production by fibroblasts.

    “This effect runs via the 5H-T2b receptor; inhibition of this receptor with terguride decreases collagen and fibronectin production by fibroblasts.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Dees, 2011, Platelet-derived serotonin links vascular disease and tissue fibrosis, J Exp Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M2 macrophages have a less pro-inflammatory and more repair oriented phenotype than classically activated M1 macrophages.

    “These cells have a less pro-inflammatory and more repair oriented phenotype than classically activated macrophages, i.e., M1 macrophages (156).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Arango Duque, 2014, Macrophage cytokines: involvement in immunity and infectious diseases, Front Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological inhibition of neutrophil elastase by sivelestat protects mice from bleomycin induced lung fibrosis, demonstrating that at least in lungs, neutrophil elastase is pro-fibrotic.

    “Furthermore, pharmacological inhibition of neutrophil elastase by sivelestat protects mice from bleomycin induced lung fibrosis (167), demonstrating that at least in lungs, neutrophil elastase is pro-fibrotic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Takemasa, 2012, A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice, Eur Respir J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mast cells produce tryptase, which stimulates fibroblast proliferation and collagen production.

    “Mast cells also produce tryptase, a serine proteinase, which, remarkably, stimulates fibroblast proliferation and collagen production (142, 160, 161), and histamine, which also”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [142] Gailit, 2001, The differentiation and function of myofibroblasts is regulated by mast cell mediators, J Invest Dermatol. source

      Not checked in the free run.

    • cites [160] Ruoss, 1991, Mast cell tryptase is a mitogen for cultured fibroblasts, J Clin Invest. source

      Not checked in the free run.

    • cites [161] Cairns, 1997, Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts, J Clin Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking the 5H-T2b receptor are protected against bleomycin-induced skin fibrosis, just as mice in which the 5H-T2b receptor is pharmacologically inhibited.

    “Importantly, mice that lack this receptor (5H-T2b-/-) are protected against bleomycin-induced skin fibrosis, just as mice in which the 5H-T2b, receptor is pharmacologically inhibited (149).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Dees, 2011, Platelet-derived serotonin links vascular disease and tissue fibrosis, J Exp Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mast cells can directly interact with skin (myo)fibroblasts, and this facilitates their role in fibrosis.

    “Interestingly, mast cells can directly interact with skin (myo) fibroblasts, and this facilitates their role in fibrosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Pincha, 2018, PAI1 mediates fibroblast-mast cell interactions in skin fibrosis, J Clin Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, neutrophil elastase directly stimulates myofibroblast formation, proliferation, and contractility.

    “Mice lacking this enzyme are protected against asbestos-induced lung fibrosis, and in vitro neutrophil elastase directly stimulates myofibroblasts formation, proliferation, and contractility (166).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Gregory, 2015, Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis, J Leukocyte Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, deletion of lung macrophages using liposomal clodronate reduces bleomycin induced lung fibrosis, and a similar effect is obtained if circulating monocytes are depleted using liposomal clodronate.

    “The importance of macrophages in regulating fibrosis is demonstrated by the observation that in mice, deletion of lung macrophages using liposomal chlodronate reduces bleomycin induced lung fibrosis, and a similar effect is obtained if circulating monocytes are depleted using liposomal chlodronate (169).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Gibbons, 2011, Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis, Am J Resp Critic Care Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serpine1 is chemotactic for mast cells and induces the expression of ICAM1 in fibroblasts, which is needed for mast cells to adhere to fibroblasts.

    “Apart from the aforementioned role as inhibitor of plasmin activation, this protein is a chemotactic for mast cells and induces the expression of intercellular adhesion molecule 1 (ICAM1) in fibroblasts, which is needed for mast cells to adhere to fibroblasts (162).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Pincha, 2018, PAI1 mediates fibroblast-mast cell interactions in skin fibrosis, J Clin Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reactive oxygen species activate fibroblasts and stimulate fibrosis.

    “Reactive oxygen species activate fibroblasts and stimulate fibrosis (165).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Richter, 2016, Reactive oxygen species and fibrosis: further evidence of a significant liaison, Cell Tissue Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with tocilizumab for 24 weeks decreased fibroblast protein production, migration, and contractility compared to baseline.

    “Treatment with tocilizumab for 24 weeks decreased fibroblast protein production, migration and contractility compared to baseline (98).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Denton, 2018, Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nintedanib protects mice and rats against bleomycin-induced lung fibrosis and lowers lymphocytes and neutrophils but not macrophages in bronchoalveolar lavage liquid in this model.

    “In vivo, nintedanib protects mice and rats against bleomycin-induced lung fibrosis (195, 196), and lowers the amount of lymphocytes and neutrophils but not macrophages in bronchoalveolar lavage liquid in this model.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [195] Wollin, 2015, Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis, Eur Respir J. source

      Not checked in the free run.

    • cites [196] Wollin, 2014, Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis, J Pharmacol Exp Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Th2 cells produce pro-fibrotic cytokines IL-4, IL-5, and IL-13, which directly stimulate fibroblasts but also induce the formation of alternatively activated macrophages.

    “These cells produce the pro-fibrotic cytokines IL-4, IL-5, and IL-13, which directly stimulate fibroblasts but also induce the formation of alternatively activated macrophages (172, 173).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] O'Reilly, 2012, T cells in systemic sclerosis: a reappraisal, Rheumatology source

      Not checked in the free run.

    • cites [173] Barron, 2011, Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages, Am J physiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The effects of anti-integrin α5β1/α5β3 antibodies are mimicked by a TGFβ-inhibiting antibody, suggesting these effects possibly run via inhibition of TGFβ activation.

    “The effects of these antibodies are mimicked by a TGFβ inhibiting antibody, illustrating that these effects possibly run via inhibition of TGFβ activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Gerber, 2013, Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nintedanib lowers myofibroblast count and skin fibrosis in bleomycin-induced skin fibrosis in mice.

    “Furthermore, it lowers the myofibroblasts count and skin fibrosis in bleomycin induced skin fibrosis in mice (197).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Huang, 2016, Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nintedanib inhibits proliferation and motility induced by FGF and PDGF and inhibits TGFβ-induced collagen deposition in lung fibroblasts in vitro.

    “In lung fibroblasts in vitro, nintedanib inhibits proliferation and motility as induced by FGF and PDGF, but also inhibits TGFβ-induced collagen deposition (195).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [195] Wollin, 2015, Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis, Eur Respir J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Imatinib reduces collagen production in skin fibroblasts and protects mice against bleomycin-induced fibrosis via reduction of myofibroblast formation and matrix deposition.

    “This compound also reduces collagen production in skin fibroblasts, and also protects mice against bleomycin induced fibrosis via reduction of myofibroblasts formation and matrix deposition (200).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Distler, 2007, Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of Th1 cells is attributed to their production of IFNγ, which directly inhibits myofibroblast formation and function, but also directs macrophage polarization away from the pro-fibrotic, alternatively activated (M2) phenotype.

    “This effect of Th1 cells is attributed to their production of IFNγ, which directly inhibits myofibroblast formation and function, but also directs macrophage polarization away from the pro-fibrotic, alternatively activated (M2) phenotype.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Kolahian, 2016, Immune mechanisms in pulmonary fibrosis, Am J Respir Cell Mol Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SSc, both the killing ability and stimulation-dependent IFNγ production of NK cells have been reported to be reduced.

    “However, in SSc, both the killing ability and stimulation-dependent IFNγ production of NK cells has been reported to be reduced (171).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Horikawa, 2005, Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity, J Invest Dermatol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tocilizumab is a humanized antibody directed against the IL-6 receptor and is currently enrolled in a phase III trial for SSc therapy.

    “Tocilizumab is a humanized antibody directed against the IL-6 receptor and currently enrolled in a phase III trial for SSc therapy (98).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Denton, 2018, Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the placebo group, gene expression was not significantly altered over 24 weeks, whereas in the tocilizumab treated group 2,136 genes were significantly differentially expressed.

    “Furthermore, a large effect between the tocilizumab and placebo treated groups was observed on gene expression profile; in the placebo group, gene expression was not significantly altered over 24 weeks, whereas in the tocilizumab treated group 2,136 genes were significantly differentially expressed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Denton, 2018, Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For the stimulatory effect of B cells on fibroblast activity, cell-cell contact was required, as the use of a transwell system negated the stimulatory effect.

    “For this effect cell-cell contact was required, as the use of a transwell system negated the stimulatory effect of B cells on fibroblast activity (175).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Francois, 2013, B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis, Arthrit Res Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low-dose imatinib in an open label study for interstitial lung disease in SSc patients unresponsive to cyclophosphamide stabilized lung function but had no effect on skin.

    “A low dose of imatinib has also been tested in an open label study for treatment of intestitial lung disease in SSc patients unresponsive to cyclophosphamide (184), and was reported to stabilize lung function but again had no effect on skin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Fraticelli, 2014, Imatinib in Scleroderma Italian Study, Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study, Arthrit Res Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SSc skin fibroblasts, nintedanib prevents proliferation and motility and lowers αSMA expression.

    “In SSc skin fibroblasts, nintedanib also prevents proliferation and motility and lowers the expression of αSMA (197).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Huang, 2016, Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis, Ann Rheum Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SSc, the extent of Th2 polarization directly positively correlates with active interstitial lung disease (i.e., lung fibrosis), supporting a role of Th2 cells in this process.

    “SSc is characterized by Th2 polarization, i.e., a Th2 cytokine profile in blood, and importantly, in SSc, the extent of Th2 polarization directly positively correlates with active interstitial lung disease (i.e., lung fibrosis), supporting for a role of Th2 cells in this process (132).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Boin, 2008, T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease, Arthritis Rheum. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fresolimumab, a high-affinity TGFβ-inactivating monoclonal antibody, reduced TGFβ-dependent gene expression in skin biopsies and improved modified Rodnan skin score in SSc patients in a small open label single-center study.

    “In a small open label single center study, Fresolimumab (180), a high affinity TGFβ inactivating monoclonal antibody was recently tested in SSc patients, and reduced TGFβ dependent gene expression in skin biopsies and improved modified Rodnan skin score (180).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [180] Rice, 2015, Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients, J Clin Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    B lymphocytes can promote fibrosis; co-culture of B cells with skin fibroblasts induced the expression of collagen and αSMA by the latter.

    “Finally, B lymphocytes have also been demonstrated to be able to promote fibrosis; co-culture of B cells with skin fibroblasts induced the expression of collagen and αSMA by the latter (175).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Francois, 2013, B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis, Arthrit Res Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pirfenidone reduces fibroblast proliferation and attenuates TGFβ-induced αSMA and collagen production in primary skin fibroblasts.

    “Furthermore, this compound reduces fibroblast proliferation and attenuates TGFβ-induced αSMA and collagen production in primary skin fibroblast (192, 193).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [192] Conte, 2014, Effect of pirfenidone on proliferation, TGF-beta-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts, Eur J Pharm Sci. source

      Not checked in the free run.

    • cites [193] Lehtonen, 2016, Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis, Resp Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Abatacept can possibly alleviate inflammation-driven fibrosis, but not by directly targeting myofibroblasts.

    “These results indicate that abatacept can possibly eleviate inflammation driven fibrosis, but not by directly targeting myofibroblasts.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Abatacept does not affect skin fibrosis in the murine Tsk1 model of SSc nor in bleomycin-induced skin fibrosis in SCID mice.

  • May combine two claims.

    Premisecitation

    In bleomycin lung fibrosis, activation of cannabinoid receptor type 2 signaling by JWH133 lowered inflammatory response and extracellular collagen deposition, accompanied by reduced TGFβ in blood.

    “In addition, in bleomycin lung fibrosis activation of canabinoid receptor type 2 signaling by JWH133 lowered both the inflammatory response and extracellular collagen deposition, which was accompanied by reduced levels of TGFβ in blood (206).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Fu, 2017, Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice, Oncotarget source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early SSc skin is characterized by perivascular T cell infiltrates, and late-stage SSc patients have increased Th2 cell activation and express pro-fibrotic cytokines IL-4, IL-5, IL-6, and IL-13.

    “Early SSc skin is characterized by perivascular T cell infiltrates (172), and (late stage) SSc patients have increased Th2 cell activation (Th2 polarization) and these cells express the pro-fibrotic cytokines IL-4, IL-5, IL-6, and IL-13 (172).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] O'Reilly, 2012, T cells in systemic sclerosis: a reappraisal, Rheumatology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Multiple drugs targeting myofibroblasts are currently in phase 3 trials.

    “Currently multiple drugs doing just that are in phase 3 trials, giving hope for the future of SSc treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Skin fibroblasts express CBr2, and this expression is increased in SSc.

    “Skin fibroblasts express CBr2, and this expression is increased in SSc (204).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Garcia-Gonzalez, 2009, Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts, Rheumatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulation of SSc skin fibroblasts with WIN55,212-2 lowers matrix production, myofibroblast formation, and production of TGFβ, CTGF, and IL-6.

    “Stimulation of SSc skin fibroblasts with the synthetic cannabinoid WIN55,212-2 lowers matrix production, myofibroblast formation, and production of TGFβ, CTGF, and IL-6 (204).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Garcia-Gonzalez, 2009, Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts, Rheumatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In bleomycin-induced skin fibrosis in mice, abatacept lowers influx of monocytes, T cells, and B cells into lesional areas, lowers IL-6 and IL-10 levels, and lowers skin fibrosis.

    “In bleomycin induced skin fibrosis in mice, abatacept lowers the influx of monocytes, T cells and B cells into lesional areas, lowers IL-6 and IL-10 levels and lowers skin fibrosis (207).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [207] Ponsoye, 2016, Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis, Ann Rheum Dis. source

      Not checked in the free run.

81 of 81

  • The paper relies on this without support.

    No targeted disease-modifying therapy for SSc is currently available.

    “Unfortunately, to date, no targeted disease-modifying therapy is available, resulting in a large unmet medical need.”

  • The paper relies on this without support.

    The lack of targeted therapy for SSc is partly due to a lack of understanding of its pathophysiology.

    “The lack of targeted therapy for SSc is partly due to a lack of understanding of its pathophysiology.”

  • The paper relies on this without support.

    TGFβ induces the expression of ET-1, CTGF, and VEGF in myofibroblasts.

    “Of note, TGFβ induces the expression of ET-1, CTGF, and VEGF in myofibroblasts, indicating that this growth factor lays at the heart of the expression of these factors.”

  • The paper relies on this without support.

    PI3K/AKT signaling facilitates myofibroblast survival by inhibiting BAX through phosphorylation and inactivation of BAD.

    “This pathway facilitates myofibroblasts survival by inhibiting the activity of BAX. It does so by inactivating bcl2-associated agonist of cell death (BAD) via phosphorylation, after which this protein can no longer inhibit the function of anti-apoptotic proteins such as BCL2-XL.”

  • The paper relies on this without support.

    Putative drivers of pericyte to myofibroblast transition are VEGF, PDGF, and TGFβ.

    “Putative drivers of this transition are VEGF, PDGF, and TGFβ.”

  • The paper relies on this without support.

    Fibrocytes can originate from monocytes.

    “Of note, fibrocytes can originate from monocytes, and, importantly, SSc monocytes display increased maturation toward myofibroblasts as indicated by αSMA expression when compared to monocytes from healthy controls (87).”

  • The paper relies on this without support.

    Because of reduced apoptosis and increased formation, myofibroblast numbers are increased in SSc.

    “Because of reduced apoptosis and increased formation, myofibroblasts numbers are increased in SSc.”

  • The paper relies on this without support.

    VEGF, angiopoietins, and TGFβ are key regulators of endothelial homeostasis, and normally these factors are well balanced to maintain this homeostasis.

    “VEGF, angiopoietins, and TGFβ are all key regulators of endothelial homeostasis, and normally these factors are well balanced to maintain this homeostasis.”

  • The paper relies on this without support.

    Myofibroblast survival, formation, and function are all increased in SSc.

    “Myofibroblast survival, formation, and function are all increased in SSc.”

  • The paper relies on this without support.

    Abatacept does not affect skin fibrosis in the murine Tsk1 model of SSc nor in bleomycin-induced skin fibrosis in SCID mice.

    “Importantly, abatacept does not affect skin fibrosis in the murine Tsk1 model of SSc which is less dependent on inflammation nor in bleomycin induced skin fibrosis in SCID mice which lack T cells.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Activation of myofibroblasts is part of physiological wound repair; in chronic injury and inflammatory fibrotic conditions, persistent activation exacerbates disease progression.

    “Activation of myofibroblasts is itself part of physiological wound repair following tissue injury, whereas in chronic injury and inflammatory fibrotic conditions their persistent activation exacerbates the disease progression [132,133,134,135].”

    From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [134]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Tofacitinib trial phase differs between the table and text

    Minor

    Table 3 lists the ongoing tofacitinib trial as phase III, while the accompanying text calls it a phase I/II trial.

  • Different trials share the same trial identifier

    Minor

    Table 3 assigns NCT02453256 to both GSK2330811 and tofacitinib, despite listing different compounds, phases, durations, and patient numbers for the two trials.

2 of 2

The citation lists haven’t been fetched yet

References 210 · Cited by 153

Research works printed but not linked: 7

  1. Barnes, 2012, Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers, Curr Opin Rheumatol., 24, 165, 10.1097/BOR.0b013e32834ff2e8 · DOI
  2. Ramos, 2015, Genetics of systemic sclerosis: recent advances, Curr Opin Rheumatol., 27, 521, 10.1097/BOR.0000000000000214 · DOI
  3. Battegay, 1995, TNF-alpha stimulation of fibroblast proliferation, J Immunol., 154, 6040, 10.4049/jimmunol.154.11.6040 · DOI
  4. Rosenbloom, 1986, Inhibition of excessive scleroderma fibroblast collagen production by recombinant gamma-interferon, Arthritis Rheum., 29, 851, 10.1002/art.1780290706 · DOI · Paper page
  5. Krieg, 2009, Skin disease: a cardinal feature of systemic sclerosis, Rheumatology, 48, 4, 10.1093/rheumatology/kep108 · DOI · Paper page
  6. Postlethwaite, 2008, A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I, Arthritis Rheum., 58, 1810, 10.1002/art.23501 · DOI
  7. Denton, 2007, Cat-192 Study, and C, Arthritis Rheum., 56, 323, 10.1002/art.22289 · DOI

Authors
van Caam, A., Vonk, M., van den Hoogen, F., van Lent, P., & van der Kraan, P.
Affiliations
Radboud University Nijmegen (NL)
ORCID
Vonk, Madelon
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-11-13
Volume
9
Pages
2452-2452
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.02452
PMC
PMC6242950
OpenAlex
W2901760304
Semantic Scholar
60a7a64dc48035cae660e0befa24f501482efa0c
Cited by
153
References
210
Citations by year
2026: 12 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 21 · 2021: 33 · 2020: 23 · 2019: 11
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
  • Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
Keywords
systemic sclerosis, myofibroblasts, fibrosis, vasculopathy, extracellular matrix, type I collagen, mast cells, innate immunity, autoimmunity, therapeutic target
MeSH terms
Extracellular Matrix, Humans, Immunity, Innate, Killer Cells, Natural, Macrophages, Mast Cells, Neutrophils, Scleroderma, Systemic, Cytokines, Apoptosis, Th2 Cells, Collagen Type I, Myofibroblasts

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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