International Journal of Molecular Sciences

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14 pages, 9132 KiB

Open AccessArticle

Endothelial Cells Tissue-Specific Origins Affects Their Responsiveness to TGF-β2 during Endothelial-to-Mesenchymal Transition

by Fernanda Ursoli Ferreira, Lucas Eduardo Botelho Souza, Carolina Hassibe Thomé, Mariana Tomazini Pinto, Clarice Origassa, Suellen Salustiano, Vitor Marcel Faça, Niels Olsen Câmara, Simone Kashima and Dimas Tadeu Covas

Int. J. Mol. Sci. 2019, 20(3), 458; https://doi.org/10.3390/ijms20030458 - 22 Jan 2019

Cited by 24 | Viewed by 5333

Abstract

The endothelial-to-mesenchymal transition (EndMT) is a biological process where endothelial cells (ECs) acquire a fibroblastic phenotype after concomitant loss of the apical-basal polarity and intercellular junction proteins. This process is critical to embryonic development and is involved in diseases such as fibrosis and [...] Read more.

The endothelial-to-mesenchymal transition (EndMT) is a biological process where endothelial cells (ECs) acquire a fibroblastic phenotype after concomitant loss of the apical-basal polarity and intercellular junction proteins. This process is critical to embryonic development and is involved in diseases such as fibrosis and tumor progression. The signaling pathway of the transforming growth factor β (TGF-β) is an important molecular route responsible for EndMT activation. However, it is unclear whether the anatomic location of endothelial cells influences the activation of molecular pathways responsible for EndMT induction. Our study investigated the molecular mechanisms and signaling pathways involved in EndMT induced by TGF-β2 in macrovascular ECs obtained from different sources. For this purpose, we used four types of endothelial cells (coronary artery endothelial cells, CAECs; primary aortic endothelial cells PAECs; human umbilical vein endothelia cells, HUVECs; and human pulmonary artery endothelial cells, HPAECs) and stimulated with 10 ng/mL of TGF-β2. We observed that among the ECs analyzed in this study, PAECs showed the best response to the TGF-β2 treatment, displaying phenotypic changes such as loss of endothelial marker and acquisition of mesenchymal markers, which are consistent with the EndMT activation. Moreover, the PAECs phenotypic transition was probably triggered by the extracellular signal–regulated kinases 1/2 (ERK1/2) signaling pathway activation. Therefore, the anatomical origin of ECs influences their ability to undergo EndMT and the selective inhibition of the ERK pathway may suppress or reverse the progression of diseases caused or aggravated by the involvement EndMT activation. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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12 pages, 1491 KiB

Open AccessArticle

Protective Actions of Anserine Under Diabetic Conditions

by Verena Peters, Vittorio Calabrese, Elisabete Forsberg, Nadine Volk, Thomas Fleming, Hans Baelde, Tim Weigand, Christian Thiel, Angela Trovato, Maria Scuto, Sergio Modafferi and Claus Peter Schmitt

Int. J. Mol. Sci. 2018, 19(9), 2751; https://doi.org/10.3390/ijms19092751 - 13 Sep 2018

Cited by 60 | Viewed by 5658

Abstract

Background/Aims: In rodents, carnosine treatment improves diabetic nephropathy, whereas little is known about the role and function of anserine, the methylated form of carnosine. Methods: Antioxidant activity was measured by oxygen radical absorbance capacity and oxygen stress response in human renal tubular cells [...] Read more.

Background/Aims: In rodents, carnosine treatment improves diabetic nephropathy, whereas little is known about the role and function of anserine, the methylated form of carnosine. Methods: Antioxidant activity was measured by oxygen radical absorbance capacity and oxygen stress response in human renal tubular cells (HK-2) by RT-PCR and Western-Immunoblotting. In wildtype (WT) and diabetic mice (db/db), the effect of short-term anserine treatment on blood glucose, proteinuria and vascular permeability was measured. Results: Anserine has a higher antioxidant capacity compared to carnosine (p < 0.001). In tubular cells (HK-2) stressed with 25 mM glucose or 20–100 µM hydrogen peroxide, anserine but not carnosine, increased intracellular heat shock protein (Hsp70) mRNA and protein levels. In HK-2 cells stressed with glucose, co-incubation with anserine also increased hemeoxygenase (HO-1) protein and reduced total protein carbonylation, but had no effect on cellular sirtuin-1 and thioredoxin protein concentrations. Three intravenous anserine injections every 48 h in 12-week-old db/db mice, improved blood glucose by one fifth, vascular permeability by one third, and halved proteinuria (all p < 0.05). Conclusion: Anserine is a potent antioxidant and activates the intracellular Hsp70/HO-1 defense system under oxidative and glycative stress. Short-term anserine treatment in diabetic mice improves glucose homeostasis and nephropathy. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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22 pages, 8033 KiB

Open AccessArticle

Effects of Er:YAG and Diode Laser Irradiation on Dental Pulp Cells and Tissues

by Shunjiro Yamakawa, Takahiko Niwa, Takeo Karakida, Kazuyuki Kobayashi, Ryuji Yamamoto, Risako Chiba, Yasuo Yamakoshi and Noriyasu Hosoya

Int. J. Mol. Sci. 2018, 19(8), 2429; https://doi.org/10.3390/ijms19082429 - 17 Aug 2018

Cited by 21 | Viewed by 6314

Abstract

Vital pulp therapy (VPT) is to preserve the nerve and maintain healthy dental pulp tissue. Laser irradiation (LI) is beneficial for VPT. Understanding how LI affects dental pulp cells and tissues is necessary to elucidate the mechanism of reparative dentin and dentin regeneration. [...] Read more.

Vital pulp therapy (VPT) is to preserve the nerve and maintain healthy dental pulp tissue. Laser irradiation (LI) is beneficial for VPT. Understanding how LI affects dental pulp cells and tissues is necessary to elucidate the mechanism of reparative dentin and dentin regeneration. Here, we show how Er:YAG-LI and diode-LI modulated cell proliferation, apoptosis, gene expression, protease activation, and mineralization induction in dental pulp cells and tissues using cell culture, immunohistochemical, genetic, and protein analysis techniques. Both LIs promoted proliferation in porcine dental pulp-derived cell lines (PPU-7), although the cell growth rate between the LIs was different. In addition to proliferation, both LIs also caused apoptosis; however, the apoptotic index for Er:YAG-LI was higher than that for diode-LI. The mRNA level of odontoblastic gene markers—two dentin sialophosphoprotein splicing variants and matrix metalloprotease (MMP)20 were enhanced by diode-LI, whereas MMP2 was increased by Er:YAG-LI. Both LIs enhanced alkaline phosphatase activity, suggesting that they may help induce PPU-7 differentiation into odontoblast-like cells. In terms of mineralization induction, the LIs were not significantly different, although their cell reactivity was likely different. Both LIs activated four MMPs in porcine dental pulp tissues. We helped elucidate how reparative dentin is formed during laser treatments. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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13 pages, 4851 KiB

Open AccessArticle

Melatonin Protects against Lung Fibrosis by Regulating the Hippo/YAP Pathway

by Xiaoguang Zhao, Jian Sun, Wei Su, Huitong Shan, Bowen Zhang, Yining Wang, Azaliia Shabanova, Hongli Shan and Haihai Liang

Int. J. Mol. Sci. 2018, 19(4), 1118; https://doi.org/10.3390/ijms19041118 - 9 Apr 2018

Cited by 52 | Viewed by 10119

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial pneumonia with high mortality. Melatonin, a hormone predominantly secreted by the pineal gland, has been reported to participate in the process of IPF. However, the mechanisms underlying the effect of melatonin in pulmonary fibrosis [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial pneumonia with high mortality. Melatonin, a hormone predominantly secreted by the pineal gland, has been reported to participate in the process of IPF. However, the mechanisms underlying the effect of melatonin in pulmonary fibrosis have not been elucidated to date. This study was designed to evaluate the anti-fibrotic role of melatonin in pulmonary fibrosis and to elucidate the potential mechanisms. We observed that melatonin markedly attenuated bleomycin (BLM)-induced experimental lung fibrosis in mice and inhibited TGF-β1-induced fibrogenesis in lung fibroblasts. Additionally, we determined that luzindole, a melatonin receptor inhibitor, reduced the anti-fibrotic effect of melatonin. Further studies showed that melatonin alleviated the translocation of YAP1 from cytoplasm to nucleus, a key downstream effector of the Hippo pathway, in vivo and in vitro by interacting with its receptor. Taken together, our results suggest that melatonin prevents lung fibrosis by inhibiting YAP1 and indicate that melatonin replacement could be a novel strategy for the treatment of lung fibrosis. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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Review

Jump to: Research

20 pages, 4940 KiB

Open AccessReview

TGF-β Signaling and the Epithelial-Mesenchymal Transition during Palatal Fusion

by Akira Nakajima, Charles F. Shuler, Alexander O. D. Gulka and Jun-ichi Hanai

Int. J. Mol. Sci. 2018, 19(11), 3638; https://doi.org/10.3390/ijms19113638 - 19 Nov 2018

Cited by 32 | Viewed by 7583

Abstract

Signaling by transforming growth factor (TGF)-β plays an important role in development, including in palatogenesis. The dynamic morphological process of palatal fusion occurs to achieve separation of the nasal and oral cavities. Critically and specifically important in palatal fusion are the medial edge [...] Read more.

Signaling by transforming growth factor (TGF)-β plays an important role in development, including in palatogenesis. The dynamic morphological process of palatal fusion occurs to achieve separation of the nasal and oral cavities. Critically and specifically important in palatal fusion are the medial edge epithelial (MEE) cells, which are initially present at the palatal midline seam and over the course of the palate fusion process are lost from the seam, due to cell migration, epithelial-mesenchymal transition (EMT), and/or programed cell death. In order to define the role of TGF-β signaling during this process, several approaches have been utilized, including a small interfering RNA (siRNA) strategy targeting TGF-β receptors in an organ culture context, the use of genetically engineered mice, such as Wnt1-cre/R26R double transgenic mice, and a cell fate tracing through utilization of cell lineage markers. These approaches have permitted investigators to distinguish some specific traits of well-defined cell populations throughout the palatogenic events. In this paper, we summarize the current understanding on the role of TGF-β signaling, and specifically its association with MEE cell fate during palatal fusion. TGF-β is highly regulated both temporally and spatially, with TGF-β3 and Smad2 being the preferentially expressed signaling molecules in the critical cells of the fusion processes. Interestingly, the accessory receptor, TGF-β type 3 receptor, is also critical for palatal fusion, with evidence for its significance provided by Cre-lox systems and siRNA approaches. This suggests the high demand of ligand for this fine-tuned signaling process. We discuss the new insights in the fate of MEE cells in the midline epithelial seam (MES) during the palate fusion process, with a particular focus on the role of TGF-β signaling. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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12 pages, 587 KiB

Open AccessReview

Discovery of Heterotopic Bone-Inducing Activity in Hard Tissues and the TGF-β Superfamily

by Takenobu Katagiri, Sho Tsukamoto, Yutaka Nakachi and Mai Kuratani

Int. J. Mol. Sci. 2018, 19(11), 3586; https://doi.org/10.3390/ijms19113586 - 13 Nov 2018

Cited by 10 | Viewed by 4838

Abstract

Bone is a unique organ because it can be experimentally induced in soft tissues by implanting a single growth factor, bone morphogenetic protein (BMP). Heterotopic bone-inducing activity was found in demineralized bone matrix in 1965. The characterization of this activity in bone enabled [...] Read more.

Bone is a unique organ because it can be experimentally induced in soft tissues by implanting a single growth factor, bone morphogenetic protein (BMP). Heterotopic bone-inducing activity was found in demineralized bone matrix in 1965. The characterization of this activity in bone enabled the purification and molecular cloning of BMPs and showed that they are members of the transforming growth factor-β (TGF-β) superfamily. Assay systems developed for this bone-inducing activity revealed the molecular mechanisms of the intracellular signaling of members of the superfamily, including BMPs. Moreover, they are being applied to elucidate molecular mechanisms and to develop novel therapeutics for a disease caused by an abnormality in BMP signaling. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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17 pages, 1097 KiB

Open AccessReview

Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

by Anna Schliermann and Joachim Nickel

Int. J. Mol. Sci. 2018, 19(10), 3220; https://doi.org/10.3390/ijms19103220 - 18 Oct 2018

Cited by 20 | Viewed by 5735

Abstract

Ontogeny of higher organisms as well the regulation of tissue homeostasis in adult individuals requires a fine-balanced interplay of regulating factors that individually trigger the fate of particular cells to either stay undifferentiated or to differentiate towards distinct tissue specific lineages. In some [...] Read more.

Ontogeny of higher organisms as well the regulation of tissue homeostasis in adult individuals requires a fine-balanced interplay of regulating factors that individually trigger the fate of particular cells to either stay undifferentiated or to differentiate towards distinct tissue specific lineages. In some cases, these factors act synergistically to promote certain cellular responses, whereas in other tissues the same factors antagonize each other. However, the molecular basis of this obvious dual signaling activity is still only poorly understood. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) are two major signal protein families that have a lot in common: They are both highly preserved between different species, involved in essential cellular functions, and their ligands vastly outnumber their receptors, making extensive signal regulation necessary. In this review we discuss where and how BMP and FGF signaling cross paths. The compiled data reflect that both factors synchronously act in many tissues, and that antagonism and synergism both exist in a context-dependent manner. Therefore, by challenging a generalization of the connection between these two pathways a new chapter in BMP FGF signaling research will be introduced. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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9 pages, 379 KiB

Open AccessReview

The Role of the TGFβ Receptor Signaling Pathway in Adult Beta Cell Proliferation

by Yinan Jiang, Shane Fischbach and Xiangwei Xiao

Int. J. Mol. Sci. 2018, 19(10), 3136; https://doi.org/10.3390/ijms19103136 - 12 Oct 2018

Cited by 13 | Viewed by 5770

Abstract

Diabetes is a global epidemic and affects millions of individuals in the United States. Devising novel treatments for diabetes continues to be a great medical challenge. Postnatal beta cell growth or compensation is largely attributed to beta cell proliferation, which declines continuously with [...] Read more.

Diabetes is a global epidemic and affects millions of individuals in the United States. Devising novel treatments for diabetes continues to be a great medical challenge. Postnatal beta cell growth or compensation is largely attributed to beta cell proliferation, which declines continuously with age. To boost beta cell proliferation to regenerate an adequate functional mass, there is a need to understand the signaling pathways that regulate beta cell proliferation for creating practical strategies to promote the process. Transforming growth factor β (TGFβ) belongs to a signaling superfamily that governs pancreatic development and the regeneration of beta cells after pancreatic diseases. TGFβ exerts its functions by activation of downstream Smad proteins and through its crosstalk with other pathways. Accumulating data demonstrate that the TGFβ receptor signaling pathway also participates in the control of beta cell proliferation. This review details the role of the TGFβ receptor signaling pathway in beta cell proliferation physiologically and in the pathogenesis of diabetes. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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13 pages, 943 KiB

Open AccessReview

Roles of TGF β and FGF Signals in the Lens: Tropomyosin Regulation for Posterior Capsule Opacity

by Eri Kubo, Teppei Shibata, Dhirendra P. Singh and Hiroshi Sasaki

Int. J. Mol. Sci. 2018, 19(10), 3093; https://doi.org/10.3390/ijms19103093 - 9 Oct 2018

Cited by 65 | Viewed by 6807

Abstract

Transforming growth factor (TGF) β and fibroblast growth factor (FGF) 2 are related to the development of posterior capsule opacification (PCO) after lens extraction surgery and other processes of epithelial–mesenchymal transition (EMT). Oxidative stress seems to activate TGF β1 largely through reactive oxygen [...] Read more.

Transforming growth factor (TGF) β and fibroblast growth factor (FGF) 2 are related to the development of posterior capsule opacification (PCO) after lens extraction surgery and other processes of epithelial–mesenchymal transition (EMT). Oxidative stress seems to activate TGF β1 largely through reactive oxygen species (ROS) production, which in turn alters the transcription of several survival genes, including lens epithelium-cell derived growth factor (LEDGF). Higher ROS levels attenuate LEDGF function, leading to down-regulation of peroxiredoxin 6 (Prdx6). TGF β is regulated by ROS in Prdx6 knock-out lens epithelial cells (LECs) and induces the up-regulation of tropomyosins (Tpms) 1/2, and EMT of LECs. Mouse and rat PCO are accompanied by elevated expression of Tpm2. Further, the expression of Tpm1/2 is induced by TGF β2 in LECs. Importantly, we previously showed that TGF β2 and FGF2 play regulatory roles in LECs in a contrasting manner. An injury-induced EMT of a mouse lens as a PCO model was attenuated in the absence of Tpm2. In this review, we present findings regarding the roles of TGF β and FGF2 in the differential regulation of EMT in the lens. Tpms may be associated with TGF β2- and FGF2-related EMT and PCO development. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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18 pages, 855 KiB

Open AccessReview

Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions

by Takeshi Tsuda

Int. J. Mol. Sci. 2018, 19(9), 2787; https://doi.org/10.3390/ijms19092787 - 17 Sep 2018

Cited by 47 | Viewed by 6032

Abstract

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic [...] Read more.

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-terminal domain. Fibulins not only participate in structural integrity of basement membrane and elastic fibers, but also serve as mediators for cellular processes and tissue remodeling as they are highly upregulated during embryonic development and certain disease processes, especially at the sites of epithelial–mesenchymal transition (EMT). Emerging studies have indicated a close relationship between fibulins and TGF-β signaling, but each fibulin plays a different role in a context-dependent manner. In this review, regulatory interactions between fibulins and TGF-β signaling are discussed. Understanding biological roles of fibulins in TGF-β regulation may introduce new insights into the pathogenesis of some human diseases. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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17 pages, 1060 KiB

Open AccessReview

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

by Nina Rol, Konda Babu Kurakula, Chris Happé, Harm Jan Bogaard and Marie-José Goumans

Int. J. Mol. Sci. 2018, 19(9), 2585; https://doi.org/10.3390/ijms19092585 - 31 Aug 2018

Cited by 85 | Viewed by 12191

Abstract

Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear [...] Read more.

Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH. This review gives a state of the art overview of disturbed signaling through the receptors of the TGF-β family with respect to vascular remodeling and cardiac effects as observed in PAH. Recent (pre)-clinical studies in which these two pathways were targeted will be discussed with an extended view on cardiovascular research fields outside of PAH, indicating novel future perspectives. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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13 pages, 641 KiB

Open AccessReview

Targeting TGF-β Signaling in Kidney Fibrosis

by Yoshitaka Isaka

Int. J. Mol. Sci. 2018, 19(9), 2532; https://doi.org/10.3390/ijms19092532 - 27 Aug 2018

Cited by 200 | Viewed by 12297

Abstract

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of [...] Read more.

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of production, activation, binding to the receptor, and intracellular signaling, have been developed. Some of them were examined in clinical studies against kidney fibrosis, and some are applied to other fibrotic diseases or cancer. Here, I review the approaches targeting TGF-β signaling in kidney fibrosis. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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17 pages, 808 KiB

Open AccessReview

Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder

by Toshifumi Sugatani

Int. J. Mol. Sci. 2018, 19(9), 2490; https://doi.org/10.3390/ijms19092490 - 23 Aug 2018

Cited by 31 | Viewed by 7425

Abstract

The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting [...] Read more.

The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-β super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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19 pages, 1312 KiB

Open AccessReview

Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis

by Hiroshi Kinashi, Yasuhiko Ito, Ting Sun, Takayuki Katsuno and Yoshifumi Takei

Int. J. Mol. Sci. 2018, 19(9), 2487; https://doi.org/10.3390/ijms19092487 - 23 Aug 2018

Cited by 63 | Viewed by 12903

Abstract

Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role [...] Read more.

Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β–VEGF-C pathway in which TGF-β promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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18 pages, 1036 KiB

Open AccessReview

TGF-β Signaling in Lung Health and Disease

by Akira Saito, Masafumi Horie and Takahide Nagase

Int. J. Mol. Sci. 2018, 19(8), 2460; https://doi.org/10.3390/ijms19082460 - 20 Aug 2018

Cited by 328 | Viewed by 16243

Abstract

Transforming growth factor (TGF)-β is an evolutionarily conserved pleiotropic factor that regulates a myriad of biological processes including development, tissue regeneration, immune responses, and tumorigenesis. TGF-β is necessary for lung organogenesis and homeostasis as evidenced by genetically engineered mouse models. TGF-β is crucial [...] Read more.

Transforming growth factor (TGF)-β is an evolutionarily conserved pleiotropic factor that regulates a myriad of biological processes including development, tissue regeneration, immune responses, and tumorigenesis. TGF-β is necessary for lung organogenesis and homeostasis as evidenced by genetically engineered mouse models. TGF-β is crucial for epithelial-mesenchymal interactions during lung branching morphogenesis and alveolarization. Expression and activation of the three TGF-β ligand isoforms in the lungs are temporally and spatially regulated by multiple mechanisms. The lungs are structurally exposed to extrinsic stimuli and pathogens, and are susceptible to inflammation, allergic reactions, and carcinogenesis. Upregulation of TGF-β ligands is observed in major pulmonary diseases, including pulmonary fibrosis, emphysema, bronchial asthma, and lung cancer. TGF-β regulates multiple cellular processes such as growth suppression of epithelial cells, alveolar epithelial cell differentiation, fibroblast activation, and extracellular matrix organization. These effects are closely associated with tissue remodeling in pulmonary fibrosis and emphysema. TGF-β is also central to T cell homeostasis and is deeply involved in asthmatic airway inflammation. TGF-β is the most potent inducer of epithelial-mesenchymal transition in non-small cell lung cancer cells and is pivotal to the development of tumor-promoting microenvironment in the lung cancer tissue. This review summarizes and integrates the current knowledge of TGF-β signaling relevant to lung health and disease. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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17 pages, 553 KiB

Open AccessReview

TGF-Beta Signaling in Bone with Chronic Kidney Disease

by Yoshiko Iwasaki, Hideyuki Yamato and Masafumi Fukagawa

Int. J. Mol. Sci. 2018, 19(8), 2352; https://doi.org/10.3390/ijms19082352 - 10 Aug 2018

Cited by 13 | Viewed by 6938

Abstract

Transforming growth factor (TGF)-β signaling is not only important in skeletal development, but also essential in bone remodeling in adult bone. The bone remodeling process involves integrated cell activities induced by multiple stimuli to balance bone resorption and bone formation. TGF-β plays a [...] Read more.

Transforming growth factor (TGF)-β signaling is not only important in skeletal development, but also essential in bone remodeling in adult bone. The bone remodeling process involves integrated cell activities induced by multiple stimuli to balance bone resorption and bone formation. TGF-β plays a role in bone remodeling by coordinating cell activities to maintain bone homeostasis. However, mineral metabolism disturbance in chronic kidney disease (CKD) results in abnormal bone remodeling, which leads to ectopic calcification in CKD. High circulating levels of humoral factors such as parathyroid hormone, fibroblast growth factor 23, and Wnt inhibitors modulate bone remodeling in CKD. Several reports have revealed that TGF-β is involved in the production and functions of these factors in bone. TGF-β may act as a factor that mediates abnormal bone remodeling in CKD. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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15 pages, 945 KiB

Open AccessReview

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

by Toshihiko Komai, Tomohisa Okamura, Mariko Inoue, Kazuhiko Yamamoto and Keishi Fujio

Int. J. Mol. Sci. 2018, 19(8), 2261; https://doi.org/10.3390/ijms19082261 - 1 Aug 2018

Cited by 25 | Viewed by 5352

Abstract

Transforming growth factor (TGF)-βs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-β have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-β. Considerable [...] Read more.

Transforming growth factor (TGF)-βs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-β have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-β. Considerable effort has been focused on understanding the molecular mechanisms of TGF-β1-mediated immune regulation, given its pivotal role in prohibiting systemic autoimmune disease. In recent years, functional similarities and differences between the TGF-β isoforms have delineated their distinct roles in the development of immunopathology and immune tolerance, with increased recent attention being focused on TGF-β3. In addition to the characteristic properties of each TGF-β isoform, recent progress has identified determinants of context-dependent functionality, including various cellular targets, cytokine concentrations, tissue microenvironments, and cytokine synergy, which combine to shape the physiological and pathophysiological roles of the TGF-βs in immunity. Controlling TGF-β production and signaling is being tested as a novel therapeutic strategy in multiple clinical trials for several human diseases. This review highlights advances in the understanding of the cellular sources, activation processes, contextual determinants, and immunological roles of TGF-β3 with comparisons to other TGF-β isoforms. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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19 pages, 1960 KiB

Open AccessReview

TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

by Norifumi Takeda, Hironori Hara, Takayuki Fujiwara, Tsubasa Kanaya, Sonoko Maemura and Issei Komuro

Int. J. Mol. Sci. 2018, 19(7), 2125; https://doi.org/10.3390/ijms19072125 - 21 Jul 2018

Cited by 102 | Viewed by 14671

Abstract

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), [...] Read more.

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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MicroRNA Control of TGF-β Signaling

by Hiroshi I. Suzuki

Int. J. Mol. Sci. 2018, 19(7), 1901; https://doi.org/10.3390/ijms19071901 - 28 Jun 2018

Cited by 111 | Viewed by 8612

Abstract

Transcriptional and post-transcriptional regulation shapes the transcriptome and proteome changes induced by various cellular signaling cascades. MicroRNAs (miRNAs) are small regulatory RNAs that are approximately 22 nucleotides long, which direct the post-transcriptional regulation of diverse target genes and control cell states. Transforming growth [...] Read more.

Transcriptional and post-transcriptional regulation shapes the transcriptome and proteome changes induced by various cellular signaling cascades. MicroRNAs (miRNAs) are small regulatory RNAs that are approximately 22 nucleotides long, which direct the post-transcriptional regulation of diverse target genes and control cell states. Transforming growth factor (TGF)-β family is a multifunctional cytokine family, which plays many regulatory roles in the development and pathogenesis of diverse diseases, including fibrotic disease, cardiovascular disease and cancer. Previous studies have shown that the TGF-β pathway includes the miRNA pathway as an important component of its downstream signaling cascades. Multiple studies of epithelial–mesenchymal transition (EMT)-related miRNAs have highlighted that miRNAs constitute the intrinsic bistable molecular switches of cell states by forming double negative feedback loops with EMT-inducing transcription factors. This may be important for understanding the reversibility of EMT at the single-cell level, the presence of distinct EMT transition states and the intra- and inter-tumor heterogeneity of cancer cell phenotypes. In the present review, I summarize the connection between TGF-β signaling and the miRNA pathway, placing particular emphasis on the regulation of miRNA expression by TGF-β signaling, the modulation of TGF-β signaling by miRNAs, the miRNA-mediated modulation of EMT and endothelial–mesenchymal transition as well as the crosstalk between miRNA and TGF-β pathways in the tumor microenvironment. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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