scholarly journals Activin A Promotes Osteoblastic Differentiation of Human Preosteoblasts through the ALK1-Smad1/5/9 Pathway

2021 ◽  
Vol 22 (24) ◽  
pp. 13491
Author(s):  
Hideki Sugii ◽  
Mhd Safwan Albougha ◽  
Orie Adachi ◽  
Hiroka Tomita ◽  
Atsushi Tomokiyo ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Alveolar Bone ◽  
Transforming Growth Factor Β ◽  
Osteoblastic Differentiation ◽  
Activin A ◽  
Type I ◽  
Periodontal Tissue ◽  
Pdl Cells ◽  
Tissue Healing ◽  
Receptor Like Kinase

Activin A, a member of transforming growth factor-β superfamily, is involved in the regulation of cellular differentiation and promotes tissue healing. Previously, we reported that expression of activin A was upregulated around the damaged periodontal tissue including periodontal ligament (PDL) tissue and alveolar bone, and activin A promoted PDL-related gene expression of human PDL cells (HPDLCs). However, little is known about the biological function of activin A in alveolar bone. Thus, this study analyzed activin A-induced biological functions in preosteoblasts (Saos2 cells). Activin A promoted osteoblastic differentiation of Saos2 cells. Activin receptor-like kinase (ALK) 1, an activin type I receptor, was more strongly expressed in Saos2 cells than in HPDLCs, and knockdown of ALK1 inhibited activin A-induced osteoblastic differentiation of Saos2 cells. Expression of ALK1 was upregulated in alveolar bone around damaged periodontal tissue when compared with a nondamaged site. Furthermore, activin A promoted phosphorylation of Smad1/5/9 during osteoblastic differentiation of Saos2 cells and knockdown of ALK1 inhibited activin A-induced phosphorylation of Smad1/5/9 in Saos2 cells. Collectively, these findings suggest that activin A promotes osteoblastic differentiation of preosteoblasts through the ALK1-Smad1/5/9 pathway and could be used as a therapeutic product for the healing of alveolar bone as well as PDL tissue.

scholarly journals Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2070
Author(s):  
Pasquale Esposito ◽  
Daniela Verzola ◽  
Daniela Picciotto ◽  
Leda Cipriani ◽  
Francesca Viazzi ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Vascular Inflammation ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Activin A ◽  
Premature Aging ◽  
High Morbidity ◽  
Type I

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

scholarly journals Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor

2007 ◽  
Vol 195 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Nina Renlund ◽  
Francis H O’Neill ◽  
LiHua Zhang ◽  
Yisrael Sidis ◽  
Jose Teixeira
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Type I ◽  
Type Ii ◽  
Activin Receptor ◽  
Activin Signaling ◽  
Endogenous Expression ◽  
Receptor Like Kinase

Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor β (TGFβ) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17–20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with 125I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFβ family.

The induction of bone formation: From bone morphogenetic proteins to the transforming growth factor-β3 protein - Redundancy, pleiotropy and the induction of cementogenesis

2021 ◽  
Vol 76 (06) ◽  
pp. 331-356
Author(s):  
Ugo Ripamont
Keyword(s):  
Growth Factor ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Alveolar Bone ◽  
Transforming Growth Factor Β ◽  
Periodontal Tissue ◽  
Rapid Induction ◽  
Furcation Defects ◽  
Expression Pathways

This review proposes to translate organogenesis and the induction of bone formation by the recombinant human transforming growth factor-β3 (hTGF-β3 ) in the Chacma baboon Papio ursinus to periodontal tissue induction and regeneration. Naturally derived highly purified osteogenic proteins of the transforming growth factor-β (TGF-β) supergene family were implanted in Class II furcation defects of the first and second mandibular molars. Additional defects in P.ursinus were treated with recombinant human osteogenic protein-1 (hOP-1, also known as bone morphogeneticprotein-7, hBMP-7) and hBMP-2, singly or in binary applications. In different studies defects were also implanted with hTGF-β3singly or in binary application with hOP-1. Harvested specimens on day 60 and 180 were processed for undecalcified histology using tungsten-carbide knives mounted on Polycut sledge’ micro-tomes or the Exakt precision cutting and grinding system.Highly purified osteogenic proteins showed the induction of Sharpey’s fibres into newly formed cementoid with foci of mineralization. hOP-1 induced substantial cementogenesis whilst hBMP-2 preferentially induced alveolar bone. Intramuscular implantation of hTGF-β3 absorbed onto coral-derived macroporous bioreactors engineered large heterotopic multicellular bone organoids. Gene expression pathways by quantitative Reverse Transcription Polymerases Chain Reaction (qRT-PCR) show that the induction of bone is via several profiled BMPs and TGF-βs expressed upon implantation of hTGF-β3 recapitulating the synergistic induction of bone as shown by binary applications of low doses of hTGF-β1 and hTGF-β3with hOP-1. The rapid induction of bone by hTGF-β3 provides theframework for a paradigmatic shift from recombinanthBMPs to hTGF-β3 in clinical contexts, provocatively operational in periodontal tissue regeneration with substantial induction of cementogenesis in angiogenesis.

scholarly journals Transforming Growth Factor β (TGFβ) Signaling via Differential Activation of Activin Receptor-like Kinases 2 and 5 during Cardiac Development

2002 ◽  
Vol 277 (51) ◽  
pp. 50183-50189 ◽  
Author(s):  
Simone M. Ward ◽  
Jay S. Desgrosellier ◽  
Xiaoli Zhuang ◽  
Joey V. Barnett ◽  
Jonas B. Galper
Keyword(s):  
Promoter Activity ◽  
Transforming Growth Factor ◽  
Cardiac Development ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
In Ovo ◽  
Activin Receptor ◽  
Atrial Cells ◽  
Tgfβ Receptors ◽  
Receptor Like Kinase

Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 daysin ovo, transforming growth factor β (TGFβ) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of Gαi2. Here in atrial cells 5 daysin ovo,TGFβ increased carbamylcholine inhibition of beat rate 2.5-fold and increased expression of Gαi2. TGFβ also stimulated Gαi2mRNA expression and promoter activity at day 5 while inhibiting them at day 14in ovo. Over the same time course expression of type I TGFβ receptors, chick activin receptor-like kinase 2 and 5 increased with a 2.3-fold higher increase in activin receptor-like kinase 2. Constitutively active activin receptor-like kinase 2 inhibited Gαi2promoter activity, whereas constitutively active activin receptor-like kinase 5 stimulated Gαi2promoter activity independent of embryonic age. In 5-day atrial cells, TGFβ stimulated the p3TP-lux reporter, which is downstream of activin receptor-like kinase 5 and had no effect on the activity of the pVent reporter, which is downstream of activin receptor-like kinase 2. In 14-day cells, TGFβ stimulated both pVent and p3TP-lux. Thus TGFβ exerts opposing effects on parasympathetic response and Gαi2expression by activating different type I TGFβ receptors at distinct stages during cardiac development.

Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2733-2743 ◽  
Author(s):  
Neil C. Robson ◽  
David J. Phillips ◽  
Tristan McAlpine ◽  
Amanda Shin ◽  
Suzanne Svobodova ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Human Monocyte ◽  
Transforming Growth Factor Β ◽  
Cd40 Ligand ◽  
Activin A ◽  
Type I ◽  
Chemokine Production ◽  
Specific Effector ◽  
Factor Α

Activin-A is a transforming growth factor-β (TGF-β) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c+ myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-α [TNF-α]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8+ T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.

SB-431542 Is a Potent and Specific Inhibitor of Transforming Growth Factor-β Superfamily Type I Activin Receptor-Like Kinase (ALK) Receptors ALK4, ALK5, and ALK7

2002 ◽  
Vol 62 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Gareth J. Inman ◽  
Francisco J. Nicolás ◽  
James F. Callahan ◽  
John D. Harling ◽  
Laramie M. Gaster ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Specific Inhibitor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Activin Receptor ◽  
Receptor Like Kinase

scholarly journals Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

2019 ◽  
Vol 12 (596) ◽  
pp. eaat7527 ◽  
Author(s):  
Jai Rautela ◽  
Laura F. Dagley ◽  
Carolina C. de Oliveira ◽  
Iona S. Schuster ◽  
Soroor Hediyeh-Zadeh ◽  
...  
Keyword(s):  
Nk Cells ◽  
Antitumor Immunity ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Nk Cell ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Cell Surface Expression ◽  
Type I ◽  
Cell Suppression

Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor–β (TGF-β) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)–dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells express the type I activin receptor ALK4, which, upon binding to its ligand activin-A, phosphorylated SMAD2/3 to suppress IL-15–mediated NK cell metabolism. Activin-A impaired human and mouse NK cell proliferation and reduced the production of granzyme B to impair tumor killing. Similar to TGF-β, activin-A also induced SMAD2/3 phosphorylation and stimulated NK cells to increase their cell surface expression of several markers of ILC1 cells. Activin-A also induced these changes in TGF-β receptor–deficient NK cells, suggesting that activin-A and TGF-β stimulate independent pathways that drive SMAD2/3-mediated NK cell suppression. Last, inhibition of activin-A by follistatin substantially slowed orthotopic melanoma growth in mice. These data highlight the relevance of examining TGF-β–independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity.

scholarly journals Activin A upregulates PTGS2 expression and increases PGE2 production in human granulosa-lutein cells

Reproduction ◽  
2016 ◽  
Vol 152 (6) ◽  
pp. 655-664 ◽  
Author(s):  
Pang-Pin Liu ◽  
Hsun-Ming Chang ◽  
Jung-Chien Cheng ◽  
Peter C K Leung
Keyword(s):  
Corpus Luteum ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Pge2 Production ◽  
Type I ◽  
Small Interfering Rnas ◽  
Luteal Function ◽  
Downstream Signaling

Activin A is one of the members of transforming growth factor-β superfamily that is expressed in human large luteal cells, and may act in an autocrine/paracrine manner to regulate luteal function. Prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme and its derivative, prostaglandin E2 (PGE2), play significant roles in the regulation of corpus luteum formation and maintenance. To date, whether activin A can induce the expression of PTGS2 and the production of PGE2 in human granulosa-lutein cells is largely unknown. The aim of this study was to examine the effects of activin A on the regulation of PTGS2 expression and PGE2 production in human granulosa-lutein cells, and to investigate the underlying signal transduction mechanisms. In this study, the immortalized (SVOG cells) and primary human granulosa-lutein cells were used as the cell models. A TGF-β/activin type I receptor inhibitor, SB431542 and small interfering RNAs were used to investigate the activin A-induced downstream signaling pathway. We have demonstrated that activin A upregulated the expression of PTGS2 and increased the production of PGE2 via an ACVR1B-mediated SMAD2/3–SMAD4 signaling pathway. Our results suggest that activin A may be involved in the modulation of human corpus luteum formation via the induction of PTGS2 expression and PGE2 production.

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