CCN2, connective tissue growth factor, stimulates collagen deposition by gingival fibroblasts via module 3 and α6‐ and β1 integrins

Heng, Edwin C.K.; Huang, Yuanyi; Black, Samuel A.; Trackman, Philip C.

doi:10.1002/jcb.20810

Cited by 96 publications

(86 citation statements)

References 53 publications

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“…The transcription complex formed by β-catenin and its DNA-binding partners known as LEF/TCF is able to promote chromatin remodeling and transcriptional initiation in a cell type-specific and context-specific manner, thus playing a key role in embryonic development, cell proliferation, differentiation, and survival. CTGF can directly bind to cell surface integrin complexes thus activating ILK signaling (13,14). CTGF can also directly bind to LRP5/6, coreceptors of Wnt (15,16).…”

Section: Ctgf β-Catenin and Neonatal Lungmentioning

confidence: 99%

“…Interestingly, we have also found that CTGFinduced lung pathology is associated with activation of β-catenin signaling, whereas treatment with CTGF antibody inhibits hyperoxia-activated β-catenin signaling. It is known that CTGF can activate β-catenin signaling by binding to cell surface integrins and lipoprotein receptor-related protein (LRP) 5/6, coreceptors of wingless/Int (Wnt) (13)(14)(15)(16). It is unknown, however, whether activation of β-catenin signaling mediates CTGF-induced alveolar and vascular pathology in neonatal mice.…”

Section: Introductionmentioning

confidence: 99%

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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: Ctgf β-Catenin and Neonatal Lungmentioning

confidence: 99%

Section: Introductionmentioning

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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“…CTGF is capable of promoting both the growth and the differentiation of most mesenchymal cells involved in endochondral ossification. This indicates that CTGF acts as a central driver in cartilage/bone growth and regeneration (Heng et al, 2006;Kanaan et al, 2006;Kubota and Takigawa, 2007;Ono et al, 2007). The importance of CTGF in skeletal development is demonstrated with the generation of CTGF knockout mice (Yamaai et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Osteogenic differentiation of mesenchymal stem cells promoted by overexpression of connective tissue growth factor

Wang¹,

Ye²,

Cheng³

et al. 2009

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Large segmental bone defect repair remains a clinical and scientific challenge with increasing interest focusing on combining gene transfection with tissue engineering techniques. The aim of this study is to investigate the effect of connective tissue growth factor (CTGF) on the proliferation and osteogenic differentiation of the bone marrow mesenchymal stem cells (MSCs). Methods: A CTGF-expressing plasmid (pCTGF) was constructed and transfected into MSCs. Then expressions of bone morphogenesis-related genes, proliferation rate, alkaline phosphatase activity, and mineralization were examined to evaluate the osteogenic potential of the CTGF gene-modified MSCs. Results: Overexpression of CTGF was confirmed in pCTGF-MSCs. pCTGF transfection significantly enhanced the proliferation rates of pCTGF-MSCs (P<0.05). CTGF induced a 7.5-fold increase in cell migration over control (P<0.05). pCTGF transfection enhanced the expression of bone matrix proteins, such as bone sialoprotein, osteocalcin, and collagen type I in MSCs. The levels of alkaline phosphatase (ALP) activities of pCTGF-MSCs at the 1st and 2nd weeks were 4.0-and 3.0-fold higher than those of MSCs cultured in OS-medium, significantly higher than those of mock-MSCs and normal control MSCs (P<0.05). Overexpression of CTGF in MSCs enhanced the capability to form mineralized nodules. Conclusion: Overexpression of CTGF could improve the osteogenic differentiation ability of MSCs, and the CTGF gene-modified MSCs are potential as novel cell resources of bone tissue engineering.

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“…Upon stimulation, CTGF is secreted into the extracellular environment where it interacts with distinct cell surface receptors, growth factors and ECM. The principal CTGF receptor is the heterodimeric cell surface integrin complexes (19)(20)(21), while integrin-linked kinase (ILK) is a key mediator of integrin signaling that interacts with the cytoplasmic domain of β integrins (22)(23)(24). Most Articles importantly, ILK signaling plays a critical role in EMT under many pathological conditions (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

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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CCN2, connective tissue growth factor, stimulates collagen deposition by gingival fibroblasts via module 3 and α6‐ and β1 integrins

Cited by 96 publications

References 53 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

Osteogenic differentiation of mesenchymal stem cells promoted by overexpression of connective tissue growth factor

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

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