Bone Morphogenetic Protein-7 Suppresses TGFβ2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention

Shu, Daisy Y.; Wojciechowski, Magdalena; Lovicu, Frank J.

doi:10.1167/iovs.16-20611

Cited by 32 publications

(31 citation statements)

References 34 publications

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“…Inhibition of Nox4 expression and its production of ROS using a pan-NADPH oxidase inhibitor, VAS2870, suppressed the progression of EMT (Das et al, 2016). Recent work in our laboratory has shown that BMP-7 can also suppress TGFβ2-induced EMT in the lens by upregulating the phosphorylation of BMP-7-responsive Smad1/5 signaling and concurrently downregulating phosphorylation of TGFβ-responsive Smad2/3 nuclear translocation (Shu et al, 2017). The inhibitory activity of BMP-7 on TGFβ2-induced lens EMT is believed to be mediated by BMP-7 target genes, Id2 and Id3 (Kowanetz et al, 2004; Saika et al, 2006; Shu et al, 2017).…”

Section: Anterior Subcapsular Cataract and Posterior Capsular Opacmentioning

confidence: 99%

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

Shu

Lovicu

2017

Progress in Retinal and Eye Research

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272

239

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Wound healing is one of the most complex biological processes to occur in life. Repair of tissue following injury involves dynamic interactions between multiple cell types, growth factors, inflammatory mediators and components of the extracellular matrix (ECM). Aberrant and uncontrolled wound healing leads to a non-functional mass of fibrotic tissue. In the eye, fibrotic disease disrupts the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition (EMT). Myofibroblasts rapidly produce excessive amounts of ECM and exert tractional forces across the ECM, resulting in the distortion of tissue architecture. Transforming growth factor-beta (TGFβ) plays a major role in myofibroblast transdifferentiation and has been implicated in numerous fibrotic eye diseases including corneal opacification, pterygium, anterior subcapsular cataract, posterior capsular opacification, proliferative vitreoretinopathy, fibrovascular membrane formation associated with proliferative diabetic retinopathy, submacular fibrosis, glaucoma and orbital fibrosis. This review serves to introduce the pathological functions of the myofibroblast in fibrotic eye disease. We also highlight recent developments in elucidating the multiple signaling pathways involved in fibrogenesis that may be exploited in the development of novel anti-fibrotic therapies to reduce ocular morbidity due to scarring.

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Section: Anterior Subcapsular Cataract and Posterior Capsular Opacmentioning

confidence: 99%

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

Shu

Lovicu

2017

Progress in Retinal and Eye Research

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272

239

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“…At the end of respective culture periods, explants were collected under RNAse-free conditions as described previously (Shu et al , 2017). RNA (200ng) was reverse-transcribed with the sensiFAST cDNA synthesis kit (Bioline, Alexandria, NSW, Australia).…”

Section: Methodsmentioning

confidence: 99%

“…RNA (200ng) was reverse-transcribed with the sensiFAST cDNA synthesis kit (Bioline, Alexandria, NSW, Australia). α-SMA primers spanning the exon-exon junction were used (see Shu et al , 2017). All qRT-PCR reactions were executed with SensiFAST SYBR No-ROX (Bioline, Australia) in the LightCycler480 (Roche Diagnostics Ltd. Frorrenstrasse, Switzerland) as described previously (Shu et al , 2017).…”

Section: Methodsmentioning

confidence: 99%

“…α-SMA primers spanning the exon-exon junction were used (see Shu et al , 2017). All qRT-PCR reactions were executed with SensiFAST SYBR No-ROX (Bioline, Australia) in the LightCycler480 (Roche Diagnostics Ltd. Frorrenstrasse, Switzerland) as described previously (Shu et al , 2017). Data was analyzed with GenEX 6.0 software (MultiD Analyses AB, Goteborg, Sweden).…”

Section: Methodsmentioning

confidence: 99%

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ERK1/2 signaling is required for the initiation but not progression of TGFβ-induced lens epithelial to mesenchymal transition (EMT)

Wojciechowski

Mahmutovic

Shu

et al. 2017

Experimental Eye Research

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Transforming Growth Factor Beta (TGFβ) potently induces lens epithelial to mesenchymal transition (EMT). The resultant mesenchymal cells resemble those found in plaques of human forms of subcapsular cataract. Smad signaling has long been implicated as the sole driving force of TGFβ-mediated activity. Rat lens epithelial explants were used to examine the role of the Smad-independent signaling, namely the MAPK/ERK1/2 signaling pathway, in the initiation and progression of TGFβ-induced EMT. Phase contrast microscopy was used to observe the morphological changes associated with TGFβ-induced EMT in this model, including cell elongation, cell membrane blebbing, cell loss as indicated by the area of bare capsule and capsular wrinkling. The levels of Smad2, Smad2/3 and ERK1/2 phosphorylation measured using western blotting confirmed that the addition of UO126 was sufficient in blocking all TGFβ-induced ERK1/2 activation, as well as reducing Smad signaling at 18 hours. Immunofluorescent labeling and further western blotting confirmed that TGFβ-induced EMT was associated with an increase in α-smooth muscle actin (α-SMA) and a reduction of E-cadherin at cell borders. Pre-treatment with UO126 was effective at blocking the TGFβ-induced EMT, as evidenced by a reduction of α-SMA expression and protein labeling, E-cadherin labeling at cell borders, and a reduction of cell loss, cell elongation and capsular wrinkling. Post-treatment with UO126 at 2 and 6 hours after TGFβ addition was also effective at blocking EMT while post-treatment with UO126 at 24 and 48 hours was not sufficient in hampering TGFβ-induced EMT. Our data implicates ERK1/2 signaling in the initiation but not the progression of TGFβ-induced EMT in rat lens epithelial cells. The tight regulation of intracellular signaling pathways such as ERK1/2 are required for the maintenance of lens epithelial cell integrity and hence tissue transparency. A greater understanding of the molecular mechanisms that drive the induction and progression of EMT in the lens will provide the basis for potential therapeutics for human cataract.

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“…BMP‐7, a member of the TGFβ superfamily, counteracts TGFβ/Smads2/3 signals by inducing expression of Id2 and Id3 (Saika et al, 2006). BMP‐7 ligand or gene transfer, as well as gene transfer of Id2/3 inhibits EMT in vitro (Yang et al, 2016; Shu et al, 2017) and in vivo (Saika et al, 2006). Moreover, Integrins, cell surface receptors, play an important role in posterior capsular opacification (PCO).…”

Section: Gene Introduction To An Injured Mouse Lensmentioning

confidence: 99%

The murine lens: A model to investigate in vivo epithelial–mesenchymal transition

Shirai

Tanaka

Lovicu

et al. 2017

Developmental Dynamics

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Epithelial–mesenchymal transition (EMT) produces myofibroblasts that contribute to the formation of fibrotic tissue with an impairment of tissue homeostasis and functionality. The crystalline lens of the eye is a unique transparent and isolated tissue. The lens vesicle becomes isolated from the surface ectoderm, its cells are all contained as they line the inner surface of the lens capsule. Clinically the formation of fibrotic tissue by the lens epithelial cells causes a type of cataract or opacification and contraction of the lens capsule postcataract surgery. Production of EMT in the intact animal lens by using specific gene transfer to the lens or experimental lens injury has been shown to be a powerful tool to investigate EMT processes. It is not easy to uncover whether the origin of the myofibroblast is epithelial cell‐derived or from other cell lineages in fibrotic tissues. However, myofibroblasts that appear in the crystalline lens pathology are totally derived from the lens epithelial cells for the reasons mentioned above. Here, we report on different animal models of lens EMT, using either transgenic approaches or injury to study the biological aspects of EMT. Developmental Dynamics 247:340–345, 2018. © 2017 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists

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Bone Morphogenetic Protein-7 Suppresses TGFβ2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention

Cited by 32 publications

References 34 publications

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

ERK1/2 signaling is required for the initiation but not progression of TGFβ-induced lens epithelial to mesenchymal transition (EMT)

The murine lens: A model to investigate in vivo epithelial–mesenchymal transition

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