Effect of Smad7 Gene Overexpression on Transforming Growth Factor β–Induced Retinal Pigment Fibrosis in a Proliferative Vitreoretinopathy Mouse Model

Saika, Shizuya; Yamanaka, Osamu; Nishikawa-Ishida, Iku; Kitano, Ai; Flanders, Kathleen C.; Okada, Yoshinori; Ohnishi, Yoshitaka; Nakajima, Yuji; Ikeda, Kazuo

doi:10.1001/archopht.125.5.647

Cited by 49 publications

(48 citation statements)

References 31 publications

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“…Smad3 can promote fibroblast proliferation and phenotypic transformation as well as synthesis and secretion of extracellular matrix, playing a key role in the TGF-β1 signal transduction (Isono et al 2002). Smad7 is the main inhibitory regulatory protein of TGF-β signal pathway, which can competitively bind the TGF-β1 receptor (Saika et al 2007). …”

Section: Discussionmentioning

confidence: 99%

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

Tan

Wang

et al. 2015

CYTOLOGIA

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SummaryThe objective of this study is to investigate the role of antisense oligodeoxynucleotide (ASODN) of basic fibroblast growth factor (bFGF) in the proliferation, differentiation and collagen synthesis of pulmonary fibroblasts (PFs) and the possible mechanism. PFs were isolated from male Wistar Rat and transfected with antisense oligodeoxynucleotide or sense oligodeoxynucleotide (SODN) of bFGF for four experimental conditions: (1) control group: PFs without TGF-β1; (2) TGF-β1 group: PFs with TGF-β1; (3) TGF-β1+ASODN group: ASODN transfected PFs with TGF-β1; and (4) TGF-β1+SODN group: SODN transfected PFs with TGF-β1. Proliferation of PFs was monitored by growth curves and MTT assays, expression of α-smooth muscle actin (α-SMA) was evaluated by immunocytochemistry, concentrations of bFGF, CTGF, and Type I collagen in culture supernatants were determined by ELISA, and mRNA expression of Smad3, Smad7 and Type I collagen in pulmonary fibroblasts was detected by RT-PCR. We found that SODN of bFGF increased cell proliferation of PFs, enhanced the expression level of bFGF, CTGF, α-SMA, type I collagen and Smad3. However, ASODN of bFGF had the opposite effects. However, Smad7 was increased in TGF-β1+SODN group but decreased in TGF-β1+ASODN group. The proliferation, differentiation, and collagen synthesis of PFs could be promoted by bFGF and inhibited by ASODN of bFGF which may be related to the regulation of TGF-β1-Smad signaling pathway.

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Section: Discussionmentioning

confidence: 99%

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

Tan

Wang

et al. 2015

CYTOLOGIA

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“…Several new strategies for prevention of ocular fibrosis, especially targeting specific signaling pathways, have been proven to be beneficial in animal models. [48][49][50] We propose that the identification and further characterization of danger signals, including HMGB1, would provide a novel …”

Section: Hmgb1 In Retinal Detachment N Arimura Et Almentioning

confidence: 99%

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

Arimura

Kii

Hashiguchi

et al. 2009

Laboratory Investigation

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High-mobility group box 1 (HMGB1) protein is a multifunctional protein, which is mainly present in the nucleus and is released extracellularly by dying cells and/or activated immune cells. Although extracellular HMGB1 is thought to be a typical danger signal of tissue damage and is implicated in diverse diseases, its relevance to ocular diseases is mostly unknown. To determine whether HMGB1 contributes to the pathogenesis of retinal detachment (RD), which involves photoreceptor degeneration, we investigated the expression and release of HMGB1 both in a retinal cell death induced by excessive oxidative stress in vitro and in a rat model of RD-induced photoreceptor degeneration in vivo. In addition, we assessed the vitreous concentrations of HMGB1 and monocyte chemoattractant protein 1 (MCP-1) in human eyes with RD. We also explored the chemotactic activity of recombinant HMGB1 in a human retinal pigment epithelial (RPE) cell line. The results show that the nuclear HMGB1 in the retinal cell is augmented by death stress and upregulation appears to be required for cell survival, whereas extracellular release of HMGB1 is evident not only in retinal cell death in vitro but also in the rat model of RD in vivo. Furthermore, the vitreous level of HMGB1 is significantly increased and is correlated with that of MCP-1 in human eyes with RD. Recombinant HMGB1 induced RPE cell migration through an extracellular signalregulated kinase-dependent mechanism in vitro. Our findings suggest that HMGB1 is a crucial nuclear protein and is released as a danger signal of retinal tissue damage. Extracellular HMGB1 might be an important mediator in RD, potentially acting as a chemotactic factor for RPE cell migration that would lead to an ocular pathological wound-healing response.

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“…30 We previously reported that loss of or blocking transforming growth factor-β (TGFβ)/Smad3 signal inhibits inflammatory fibrosis in injured cornea or conjunctiva in mice. [31][32][33][34][35][36] TGFβ uses the ALK5 receptor for phosphorylation of Smad3 and ALK1 for activation of Smad1/5/8. The signal activated by the former receptor mediates the antiangiogenic behavior and the signal by the latter exhibits the angiogenesis promotion activity in vascular endothelial cells.…”

mentioning

confidence: 99%

Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice

Iwanishi

Fujita

Tomoyose

et al. 2016

Laboratory Investigation

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We evaluated the effects of the loss of Smad3 on the development of experimental argon laser-induced choroidal neovascularization (CNV) in mice. An in vitro angiogenesis model was also used to examine the role of transforming growth factor-β1 (TGFβ1)/Smad3 signaling in vessel-like tube formation by human umbilical vein endothelial cells (HUVECs). CNV was induced in eyes of 8-12-week-old B6.129-background Smad3-deficient (KO) mice (n = 47) and wildtype (WT) mice (n = 47) by argon laser irradiation. Results showed that the size of the CNV induced was significantly smaller in KO mice as compared with WT mice at day 14 as revealed by high-resolution angiography with fluorescein isothiocyanate-dextran. Immunohistochemistry and real-time reverse transcription-polymerase chain reaction of RNA extracted from laser-irradiated choroidal tissues were conducted on specimens at specific timepoints. Invasion of macrophages (F4/80+), but not neutrophils (myeloperoxidase+), and appearance of myofibroblasts (α-smooth muscle actin+) were suppressed in laser-irradiated KO tissues. mRNA expression of inflammation-related factors, that is, vascular endothelial growth factor (VEGF), macrophage-chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and TGFβ1 in choroidal tissues was suppressed by the loss of Smad3. We then examined the effects of adding a Smad3 inhibitor, SIS3, or an ALK5 inhibitor, SB431542, on tube formation promoted by TGFβ1 or VEGF in HUVECs cocultured with fibroblast feeder. Further addition of SIS3 or SB431542 augmented vessel-like tube formation by HUVECs in the presence of TGFβ1 or VEGF.In conclusion, lack of Smad3 attenuated the growth of laser-induced CNV with suppression of inflammation by macrophages in mice. Because blocking TGFβ1/Smad3 signal stimulated the activity of angiogenesis of HUVECs in vitro, the reduction of CNV in vivo in KO mice is attributed to a decrease in growth factor levels in the tissue by the loss of Smad3.

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Effect of Smad7 Gene Overexpression on Transforming Growth Factor β–Induced Retinal Pigment Fibrosis in a Proliferative Vitreoretinopathy Mouse Model

Cited by 49 publications

References 31 publications

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

Inhibition of development of laser-induced choroidal neovascularization with suppression of infiltration of macrophages in Smad3-null mice

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