Contrasting roles for BMP-4 and ventromorphins (BMP agonists) in TGFβ-induced lens EMT

Shu, Daisy Y.; Ng, Kevin; Wishart, Tayler F.L.; Chui, Juanita N; Lundmark, Malin; Flokis, Mary; Lovicu, Frank J.

doi:10.1016/j.exer.2021.108546

Cited by 8 publications

(7 citation statements)

References 37 publications

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“…Mizutani et al demonstrated that BMP4 mRNA level continued to decrease at 12-24 h after incubation with TGF-β1 in human peritoneal mesothelial cells from the peritoneal fibrosis patients with high peritoneal transport, and its level was inversely correlated with dialysate-to-plasma ratio for creatinine (D/P Cr), which suggests a protective effect of BMP4 for both peritoneal fibrosis and membrane function [42]. BMP4 was also reported to reduce TGF-β2-induced epithelial-mesenchymal transition (EMT) and ECM production in optic nerve head cells, retinal pigment epithelial cells, and lens epithelial cells [43][44][45]. Pegorier and colleagues showed that BMP4 constrained TGF-β1-induced cellular proliferation in normal human lung fibroblasts, although its association with fibrosis was not investigated [46].…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts

Guan

Liang

et al. 2022

Eur Respir J

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Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development, however, the role of BMP4 in modulating lung fibrosis remains unknown.This study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts, and lung samples from patients with IPF.BMP4 expression was down-regulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with TGF-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. While BMP4 overexpression using AAV9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro, BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Whereas Pink1 silencing by shRNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signaling and suppression of TGF-β1-meidtaed Smad2/3 signaling in vivo and in vitro.In conclusion, strategies for enhancing BMP4 signaling may represent an effective treatment for pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts

Guan

Liang

et al. 2022

Eur Respir J

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“…More recently, BMP-4 has also emerged as a potential inhibitor of lens EMT. Work in our laboratory showed that BMP-4 can block TGFβ2-induced EMT in rat lens epithelial explants by suppressing Smad2/3 nuclear translocation [109]. The protective effect of BMP-4 has been further demonstrated in the human lens epithelial cell lines (HLE-B3), where exogenous addition of BMP-4 blocked apoptosis of lens epithelial cells under H 2 O 2 -induced oxidative stress [110].…”

Section: Bmps In Cataract Preventionmentioning

confidence: 92%

“…The protective effect of BMP-4 has been further demonstrated in the human lens epithelial cell lines (HLE-B3), where exogenous addition of BMP-4 blocked apoptosis of lens epithelial cells under H 2 O 2 -induced oxidative stress [110]. Intriguingly, small molecule agonists of BMPs, ventromorphins, were unable to suppress TGFβ2-induced lens EMT in rat lens explants, highlighting that not all approaches to promote BMP-signaling can block TGFβ2-induced lens EMT [109]. Rather, particular conditions may exist that favor the efficacy of certain BMP isoforms in blocking TGFβ2 activity.…”

Section: Bmps In Cataract Preventionmentioning

confidence: 98%

Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology

Shu

Lovicu

2021

Cells

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Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell proliferation, differentiation and morphogenesis, throughout the body. In the ocular lens, BMPs are important in orchestrating fundamental developmental processes such as induction of lens morphogenesis, and specialized differentiation of its fiber cells. Moreover, BMPs have been reported to facilitate regeneration of the lens, as well as abrogate pathological processes such as TGFβ-induced epithelial-mesenchymal transition (EMT) and apoptosis. In this review, we summarize recent insights in this topic and discuss the complexities of BMP-signaling including the role of individual BMP ligands, receptors, extracellular antagonists and cross-talk between canonical and non-canonical BMP-signaling cascades in the lens. By understanding the molecular mechanisms underlying BMP activity, we can advance their potential therapeutic role in cataract prevention and lens regeneration.

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“…In PSC and PCO, the equatorial LECs undergo EMT and migrate posteriorly to form a fibrotic plaque that impairs vision. Transforming growth factor-beta 2 (TGFβ2) is a classic inducer of EMT in the lens, resulting in the enhanced migration, contraction, and secretion of extracellular matrix proteins [ 151 , 155 , 156 ]. The induction of oxidative stress through hydrogen peroxide-induced lens EMT is mediated by the enhanced activation of the TGFβ/Smad and Wnt/β-catenin pathways [ 157 ].…”

Section: Oxidative Stress In Cataractmentioning

confidence: 99%

Role of Oxidative Stress in Ocular Diseases: A Balancing Act

et al. 2023

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Redox homeostasis is a delicate balancing act of maintaining appropriate levels of antioxidant defense mechanisms and reactive oxidizing oxygen and nitrogen species. Any disruption of this balance leads to oxidative stress, which is a key pathogenic factor in several ocular diseases. In this review, we present the current evidence for oxidative stress and mitochondrial dysfunction in conditions affecting both the anterior segment (e.g., dry eye disease, keratoconus, cataract) and posterior segment (age-related macular degeneration, proliferative vitreoretinopathy, diabetic retinopathy, glaucoma) of the human eye. We posit that further development of therapeutic interventions to promote pro-regenerative responses and maintenance of the redox balance may delay or prevent the progression of these major ocular pathologies. Continued efforts in this field will not only yield a better understanding of the molecular mechanisms underlying the pathogenesis of ocular diseases but also enable the identification of novel druggable redox targets and antioxidant therapies.

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Contrasting roles for BMP-4 and ventromorphins (BMP agonists) in TGFβ-induced lens EMT

Cited by 8 publications

References 37 publications

Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts

Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts

Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology

Role of Oxidative Stress in Ocular Diseases: A Balancing Act

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