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

2018 ◽  
Vol 19 (9) ◽  
pp. 2585 ◽  
Author(s):  
Nina Rol ◽  
Konda Kurakula ◽  
Chris Happé ◽  
Harm Bogaard ◽  
Marie-José Goumans
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Cardiovascular Research ◽  
Black Sheep ◽  
Research Fields ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial ◽  
Extended View

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.

scholarly journals GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

2020 ◽  
Vol 117 (9) ◽  
pp. 4910-4920 ◽  
Author(s):  
Joonho Suh ◽  
Na-Kyung Kim ◽  
Seung-Hoon Lee ◽  
Je-Hyun Eom ◽  
Youngkyun Lee ◽  
...  
Keyword(s):  
Bone Mass ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Biochemical Properties ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

Effects of bone morphogenetic protein 15 (BMP15) knockdown on porcine testis morphology and spermatogenesis

2020 ◽  
Vol 32 (11) ◽  
pp. 999
Author(s):  
Tao Tang ◽  
Qiyuan Lin ◽  
Yufeng Qin ◽  
Xinyu Liang ◽  
Yang Guo ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Biological Function ◽  
Transforming Growth Factor Β ◽  
Reproductive Capacity ◽  
Ovary Development ◽  
Sperm Viability ◽  
Morphogenetic Protein ◽  
Bone Morphogenetic Protein 15

Bone morphogenetic protein 15 (BMP15) is a member of the transforming growth factor-β (TGFB) superfamily that plays an essential role in mammalian ovary development, oocyte maturation and litter size. However, little is known regarding the expression pattern and biological function of BMP15 in male gonads. In this study we established, for the first time, a transgenic pig model with BMP15 constitutively knocked down by short hairpin (sh) RNA. The transgenic boars were fertile, but sperm viability was decreased. Further analysis of the TGFB/SMAD pathway and markers of reproductive capacity, namely androgen receptor and protamine 2, failed to identify any differentially expressed genes. These results indicate that, in the pig, the biological function of BMP15 in the development of male gonads is not as crucial as in ovary development. However, the role of BMP15 in sperm viability requires further investigation. This study provides new insights into the role of BMP15 in male pig reproduction.

SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2657-2665 ◽  
Author(s):  
Katarzyna Mleczko-Sanecka ◽  
Guillem Casanovas ◽  
Anan Ragab ◽  
Katja Breitkopf ◽  
Alexandra Müller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Iron Metabolism ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Protein

Abstract Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-β and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-β. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.

scholarly journals The Role of BMP Signaling in Female Reproductive System Development and Function

2021 ◽  
Vol 22 (21) ◽  
pp. 11927
Author(s):  
Esmeralda Magro-Lopez ◽  
María Ángeles Muñoz-Fernández
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Reproductive System ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
System Development ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Female Reproductive System ◽  
And Function

Bone morphogenetic proteins (BMPs) are a group of multifunctional growth factors that belong to the transforming growth factor-β (TGF-β) superfamily of proteins. Originally identified by their ability to induce bone formation, they are now known as essential signaling molecules that regulate the development and function of the female reproductive system (FRS). Several BMPs play key roles in aspects of reproductive system development. BMPs have also been described to be involved in the differentiation of human pluripotent stem cells (hPSCs) into reproductive system tissues or organoids. The role of BMPs in the reproductive system is still poorly understood and the use of FRS tissue or organoids generated from hPSCs would provide a powerful tool for the study of FRS development and the generation of new therapeutic perspectives for the treatment of FRS diseases. Therefore, the aim of this review is to summarize the current knowledge about BMP signaling in FRS development and function.

Tril dampens Nodal signaling through Pellino2- and Traf6-mediated activation of Nedd4l

2021 ◽  
Vol 118 (36) ◽  
pp. e2104661118
Author(s):  
Hyung-Seok Kim ◽  
Yangsook Song Green ◽  
Yuanyuan Xie ◽  
Jan L. Christian
Keyword(s):  
Ubiquitin Ligase ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Nodal Signaling ◽  
Vertebrate Development ◽  
Morphogenetic Protein ◽  
Membrane Compartments ◽  
Leucine Rich Repeats

Toll-like receptor 4 (Tlr) interactor with leucine-rich repeats (Tril) functions as a Tlr coreceptor to mediate innate immunity in adults. In Xenopus embryos, Tril triggers degradation of the transforming growth factor β (Tgf-ß) family inhibitor, Smad7. This enhances bone morphogenetic protein (Bmp) signaling to enable ventral mesoderm to commit to a blood fate. Here, we show that Tril simultaneously dampens Nodal signaling by catalytically activating the ubiquitin ligase NEDD4 Like (Nedd4l). Nedd4l then targets Nodal receptors for degradation. How Tril signals are transduced in a nonimmune context is unknown. We identify the ubiquitin ligase Pellino2 as a protein that binds to the cytoplasmic tail of Tril and subsequently forms a complex with Nedd4l and another E3 ligase, TNF-receptor associated factor 6 (Traf6). Pellino2 and Traf6 are essential for catalytic activation of Nedd4l, both in Xenopus and in mammalian cells. Traf6 ubiquitinates Nedd4l, which is then recruited to membrane compartments where activation occurs. Collectively, our findings reveal that Tril initiates a noncanonical Tlr-like signaling cascade to activate Nedd4l, thereby coordinately regulating the Bmp and Nodal arms of the Tgf-ß superfamily during vertebrate development.

scholarly journals Cooperative Inhibition of Bone Morphogenetic Protein Signaling by Smurf1 and Inhibitory Smads

2003 ◽  
Vol 14 (7) ◽  
pp. 2809-2817 ◽  
Author(s):  
Gyo Murakami ◽  
Tetsuro Watabe ◽  
Kunio Takaoka ◽  
Kohei Miyazono ◽  
Takeshi Imamura
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Type I ◽  
Protein Signaling ◽  
Reporter Construct ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein

Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-β type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.

scholarly journals Reovirus Activates Transforming Growth Factor β and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection

2009 ◽  
Vol 83 (10) ◽  
pp. 5035-5045 ◽  
Author(s):  
J. David Beckham ◽  
Kathryn Tuttle ◽  
Kenneth L. Tyler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Downstream Signaling ◽  
Morphogenetic Protein ◽  
The Central Nervous System

ABSTRACT Viral infections of the central nervous system (CNS) are important causes of worldwide morbidity and mortality, and understanding how viruses perturb host cell signaling pathways will facilitate identification of novel antiviral therapies. We now show that reovirus infection activates transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in a murine model of encephalitis in vivo. TGF-β receptor I (TGF-βRI) expression is increased and its downstream signaling factor, SMAD3, is activated in the brains of reovirus-infected mice. TGF-β signaling is neuroprotective, as inhibition with a TGF-βRI inhibitor increases death of infected neurons. Similarly, BMP receptor I expression is increased and its downstream signaling factor, SMAD1, is activated in reovirus-infected neurons in the brains of infected mice in vivo. Activated SMAD1 and SMAD3 were both detected in regions of brain infected by reovirus, but activated SMAD1 was found predominantly in uninfected neurons in close proximity to infected neurons. Treatment of reovirus-infected primary mouse cortical neurons with a BMP agonist reduced apoptosis. These data provide the first evidence for the activation of TGF-β and BMP signaling pathways following neurotropic viral infection and suggest that these signaling pathways normally function as part of the host's protective innate immune response against CNS viral infection.

scholarly journals TGFβ/BMP Signaling Pathway in Cartilage Homeostasis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 969 ◽  
Author(s):  
Nathalie Thielen ◽  
Peter van der Kraan ◽  
Arjan van Caam
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Cartilage Homeostasis ◽  
Cartilage Biology ◽  
Matrix Production

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease.

scholarly journals Activation of both transforming growth factor-β and bone morphogenetic protein signalling pathways upon traumatic brain injury restrains pro-inflammatory and boosts tissue reparatory responses of reactive astrocytes and microglia

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Georgios Divolis ◽  
Athanasios Stavropoulos ◽  
Maria Manioudaki ◽  
Anastasia Apostolidou ◽  
Athanasia Doulou ◽  
...  
Keyword(s):  
Brain Injury ◽  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Transforming Growth Factor Β1 ◽  
Reactive Astrocytes ◽  
Glia Cells ◽  
Morphogenetic Protein

Abstract Various ligands and receptors of the transforming growth factor-β superfamily have been found upregulated following traumatic brain injury; however, the role of this signalling system in brain injury pathophysiology is not fully characterized. To address this, we utilized an acute stab wound brain injury model to demonstrate that hallmarks of transforming growth factor-β superfamily system activation, such as levels of phosphorylated Smads, ligands and target genes for both transforming growth factor-β and bone morphogenetic protein pathways, were upregulated within injured tissues. Using a bone morphogenetic protein-responsive reporter mouse model, we showed that activation of the bone morphogenetic protein signalling pathway involves primarily astrocytes that demarcate the wound area. Insights regarding the potential role of transforming growth factor-β superfamily activation in glia cells within the injured tissues were obtained indirectly by treating purified reactive astrocytes and microglia with bone morphogenetic protein-4 or transforming growth factor-β1 and characterizing changes in their transcriptional profiles. Astrocytes responded to both ligands with considerably overlapping profiles, whereas, microglia responded selectively to transforming growth factor-β1. Novel pathways, crucial for repair of tissue-injury and blood–brain barrier, such as activation of cholesterol biosynthesis and transport, production of axonal guidance and extracellular matrix components were upregulated by transforming growth factor-β1 and/or bone morphogenetic protein-4 in astrocytes. Moreover, both ligands in astrocytes and transforming growth factor-β1 in microglia shifted the phenotype of reactive glia cells towards the anti-inflammatory and tissue reparatory ‘A2’-like and ‘M0/M2’-like phenotypes, respectively. Increased expression of selected key components of the in vitro modulated pathways and markers of ‘A2’-like astrocytes was confirmed within the wound area, suggesting that these processes could also be modulated in situ by the integrated action of transforming growth factor-β and/or bone morphogenetic protein-mediated signalling. Collectively, our study provides a comprehensive comparative analysis of transforming growth factor-β superfamily signalling in reactive astrocytes and microglia and points towards a crucial role of both transforming growth factor-β and bone morphogenetic protein pathways in modulating the inflammatory and brain injury reparatory functions of activated glia cells.

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