Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis

Sonnylal, Sonali; Xu, Shiwen; Leoni, Patricio Clark Di; Naff, Katherine A.; Pelt, Caroline S. Van; Nakamura, Hiroyuki; Leask, Andrew; Abraham, David; Bou‐Gharios, George; Crombrugghe, Benoít de

doi:10.1002/art.27382

Cited by 172 publications

(150 citation statements)

References 27 publications

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“…Sonnylal et al (20,21) demonstrated that targeted overexpression of CTGF in lung fibroblasts disrupts lung structure and induces fibrosis which affects both lung fibroblasts and epithelial cells. Our previous studies showed that targeted overexpression of CTGF in AT II cells not only disrupts alveolar and vascular development but also induces interstitial fibrosis and vascular remodeling (12).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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Background: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates β-catenin in neonatal mice. Methods: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of β-catenin, we tested the hypothesis that β-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. results: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of β-catenin signaling in CTGF lungs. Inhibition of β-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. conclusion: β-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-β-catenin signaling may provide a novel therapy for BPD. INTRODUCTIONBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants (1). Over the past four decades, the incidence of this disease has significantly increased as a result of improved survival of extremely-low-birthweight infants (2). The pathology of BPD is increasingly being recognized as a developmental arrest of the immature lung caused by injurious stimuli such as mechanical ventilation, oxygen exposure, and intrauterine or postnatal infections. Larger and simplified alveoli, decreased vascular growth, and variable interstitial fibrosis are the key pathological features observed in lungs of infants who died of BPD (1). The combination of decreased vascular growth and excessive pulmonary vascular remodeling leads to pulmonary hypertension (PH) which significantly contributes to the morbidity and mortality of these infants (3). Yet, the underlying cellular and molecular mechanisms are poorly defined, and there is no effective therapy.Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling (4). Recent studies have highlighted the potential role of CTGF in BPD development and progression. The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTG...

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Section: Discussionmentioning

confidence: 99%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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“…Constitutive expression of CTGF in fibroblasts is sufficient to cause accelerated diffuse tissue fibrosis in vivo [40]. The Ets factor, Fli1, may be of central importance in this pathway.…”

Section: The Role Of Adenosine and Its Receptors In Granulation Tissumentioning

confidence: 99%

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

Shaikh

Cronstein

2016

Purinergic Signalling

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Collagen and matrix deposition by fibroblasts is an essential part of wound healing but also contributes to pathologic remodeling of organs leading to substantial morbidity and mortality. Adenosine, a small molecule generated extracellularly from adenine nucleotides as a result of direct stimulation, hypoxia, or injury, acts via a family of classical sevenpass G protein-coupled protein receptors, A 2A and A 2B , leading to generation of cAMP and activation of downstream targets such as PKA and Epac. These effectors, in turn, lead to fibroblast activation and collagen synthesis. The regulatory actions of these receptors likely involve multiple interconnected pathways, and one of the more interesting aspects of this regulation is opposing effects at different levels of cAMP generated. Additionally, adenosine signaling contributes to fibrosis in organ-specific ways and may have opposite effects in different organs. The development of drugs that selectively target these receptors and their signaling pathways will disrupt the pathogenesis of fibrosis and slow or arrest the progression of the important diseases they underlie.

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“…Ivkovic et al (35) have shown that global knockout of CTGF results in respiratory failure and immediate death in newborn mice suggesting that endogenous CTGF in lung cells are important for embryonic lung development and newborn lung function. Sonnylal et al (31,32) demonstrated that targeted overexpression of CTGF in lung fibroblasts induces fibrosis which affects both lung fibroblasts and epithelial cells indicating that fibroblast-derived CTGF results in lung fibrosis via both autocrine Articles Shafieian et al…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, these cells expressed mesenchymal markers such as α-SMA, fibronectin, and vimentin, suggesting EMT-like changes. Sonnylal et al, have demonstrated that CTGF causes EMT-like cell fate in vivo and in vitro in the lung (31,32). They used transgenic mice with mesenchymal overexpression of CTGF driven by the collagen 1a2 promoter as well as lung epithelial cells lines A549 and SV40-T2.…”

Section: Discussionmentioning

confidence: 99%

“…Increased CTGF expression is detected in patients with lung fibrosis and bronchopulmonary dysplasia (28)(29)(30). Transgenic overexpression of CTGF in fibroblasts resulted in systemic fibrosis, including the lung (31). Furthermore, in vivo and in vitro studies have shown that expression of CTGF in lung epithelial cells or treatment with exogenous CTGF induces EMT-like changes (32).…”

Section: Introductionmentioning

confidence: 99%

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Integrin-linked kinase mediates CTGF-induced epithelial to mesenchymal transition in alveolar type II epithelial cells

Shafieian

Chen

2015

Pediatr Res

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Background: Overexpression of connective tissue growth factor (CTGF) in alveolar type II epithelial (AT II) cells disrupts alveolar structure, causes interstitial fibrosis, and upregulates integrin-linked kinase (ILK). Whether CTGF-ILK signaling induces epithelial to mesenchymal transition (EMT) in AT II cells is unknown. Methods: Transgenic mice with targeted overexpression of CTGF in AT II cells were generated utilizing the surfactant protein C (SP-C) gene promoter and doxycycline-inducible system. AT II cells were isolated from 4-wk-old CTGF-overexpressing (CTGF+) mice and control littermates, and cultured on Matrigel. Cells were transfected with ILK siRNA, and cell morphology and expression of cell differentiation markers were analyzed. results: The AT II cells from the control lungs grew in clusters and formed alveolar-like cysts and expressed SP-C. In contrast, the cells from CTGF+ lungs were spread and failed to form alveolar-like cysts. These cells expressed higher levels of CTGF, α smooth muscle actin (α-SMA), fibronectin and vimentin, the mesenchymal markers, suggesting EMT-like changes. Transfection with ILK siRNA not only dramatically attenuated ILK expression, but also decreased α-SMA expression as well as reversed cell morphological changes in CTGF+ AT II cells. conclusion: Overexpression of CTGF induces EMT in mouse primary AT II cells and this is mediated by ILK.

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Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis

Cited by 172 publications

References 27 publications

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

Integrin-linked kinase mediates CTGF-induced epithelial to mesenchymal transition in alveolar type II epithelial cells

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