scholarly journals The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva

Bone ◽  
2018 ◽  
Vol 109 ◽  
pp. 210-217 ◽  
Author(s):  
Dana M. Alessi Wolken ◽  
Vincent Idone ◽  
Sarah J. Hatsell ◽  
Paul B. Yu ◽  
Aris N. Economides
Keyword(s):  
Activin A ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone

scholarly journals The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Hui Lin ◽  
Fuli Shi ◽  
Jiayu Gao ◽  
Ping Hua
Keyword(s):  
Signaling Pathway ◽  
Genetic Disorder ◽  
Activin A ◽  
Bmp Signaling ◽  
The Body ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation

Abstract Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene ALK2 in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.

scholarly journals The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent

2017 ◽  
Vol 32 (12) ◽  
pp. 2489-2499 ◽  
Author(s):  
Jaymin Upadhyay ◽  
LiQin Xie ◽  
Lily Huang ◽  
Nanditha Das ◽  
Rachel C Stewart ◽  
...  
Keyword(s):  
Activin A ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone

scholarly journals Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Senem Aykul ◽  
Richard A Corpina ◽  
Erich J Goebel ◽  
Camille J Cunanan ◽  
Alexandra Dimitriou ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Severe Disease ◽  
Physiological Role ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Signaling Complex ◽  
Bmp Receptors

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated ‘agonist-only’ Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC’s physiological role in corresponding knock-in mice.

scholarly journals ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1

2021 ◽  
Author(s):  
Senem Aykul ◽  
Lily Huang ◽  
Lili Wang ◽  
Nanditha Das ◽  
Sandra Reisman ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Genetic Disorder ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Bone Lesions ◽  
Type I ◽  
Heterotopic Bone ◽  
Wild Type ◽  
Blocking Antibodies

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by amino acid-altering mutations in ACVR1, a type I BMP receptor. The mutations occur in the region encoding the intracellular domain of ACVR1 and bestow FOP-mutant ACVR1 with the neofuction of recognizing Activin A as an agonistic ligand. (In contrast, Activin A antagonizes BMP signaling from wild type ACVR1.) This neofuction is required for HO in FOP as inhibition of Activin A stops the initiation and progression of heterotopic bone lesions in FOP. These results unequivocally demonstrated that HO in FOP is dependent on activation of FOP-mutant ACVR1 by ligand and set the stage to explore ACVR1-blocking antibodies as an additional potential therapeutic for FOP. Surprisingly, ACVR1 antibodies stimulate - rather than inhibit - HO and induce Smad1/5/8 phosphorylation of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1, as signaling by wild type ACVR1 is inhibited by these antibodies, as is trauma-induced HO. These results uncover yet an additional novel property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as a therapeutic strategy for FOP

Fibrodysplasia Ossificans Progressiva – FOP

2018 ◽  
Vol 27 (04) ◽  
pp. 215-221
Author(s):  
R. Morhart ◽  
O. Semler ◽  
L. Seefried
Keyword(s):  
Hallux Valgus ◽  
Activin A ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Intramuskuläre Injektionen ◽  
Sind Eine

ZusammenfassungBei der Fibrodysplasia ossificans progressiva (FOP) besteht aufgrund einer aktivierenden Mutation im Gen für den Activin A Rezeptor Typ 1 (ACVR1 / ALK2), eine Prädisposition zu heterotoper Knochenbildung in Weichgeweben, insbesondere der Muskulatur. Die Prävalenz der Erkrankung wird in einer Größenordnung von 1 pro 1–2 Mio. angegeben. Klinisch kommt es intrauterin zu Fehlbildungen, z. B. zu einem bds. Hallux valgus, der bei der überwiegenden Mehrheit der Patienten bereits bei Geburt besteht. Postnatal kommt es meist in den ersten Lebensjahren beginnend im Schulter-/ Nackenbereich episodenartig bereits nach kleineren Verletzungen zu schmerzhaften Weichteilreaktionen, sogenannten flareups die nachfolgend im Sinne einer enchondralen Ossifikation verknöchern. Die Akkumulation dieser irreversiblen Verknöcherungen im Weichgewebe bedingt eine zunehmende Einschränkung der Beweglichkeit bis hin zur kompletten Einsteifung des Körpers. Letztlich kommt es durch die fortschreitende Rigidität des Thorax zu einer respiratorischen Insuffizienz und kardialer Dekompensation.Therapeutisch steht im Vordergrund die Vermeidung von Traumata als Auslöser für die Entstehung extraossären Knochengewebes, insbesondere auch der Verzicht auf unnötige iatrogene Schädigungen durch Operationen, Biopsien und intramuskuläre Injektionen. Supportiv sind eine adäquate Hilfsmittelversorgung, psychologische Unterstützung und eine analgetische Versorgung erforderlich. Im Falle eines Traumas werden kurzfristig hochdosiert Glucocorticoide empfohlen, um das Risiko und Ausmaß der flare-ups und nachfolgender Verknöcherungen zu reduzieren. Ergänzend können NSAR hilfreich sein. Derzeit werden unterschiedliche neue Therapieansätze entwickelt. Am weitesten fortgeschritten ist dabei der Retinolsäure Rezeptor Gamma (RARg) Agonist Palovarotene, der durch Interferenz mit der ALK2 vermittelten Signalkaskade einen zentralen Punkt im Pathomechanismus der Erkrankung adressiert.

An Acvr1[R258G] ‘conditional on' mouse model of atypical fibrodysplasia ossificans progressiva (FOP) is Activin A dependent

2019 ◽  
Author(s):  
Lily Huang ◽  
Chris Schoenherr ◽  
Lili Wang ◽  
Xialing Wen ◽  
Joyce McClain ◽  
...  
Keyword(s):  
Mouse Model ◽  
Activin A ◽  
Fibrodysplasia Ossificans Progressiva

scholarly journals The Role of Activin A and B and the Benefit of Follistatin Treatment in Renal Ischemia-Reperfusion Injury in Mice

2016 ◽  
Vol 2 (7) ◽  
pp. e87 ◽  
Author(s):  
Doreen Y.P. Fang ◽  
Bo Lu ◽  
Susan Hayward ◽  
David M. de Kretser ◽  
Peter J. Cowan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Activin A ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury

Abstract 172: The Role of Activin A in Maternal Diabetes-Induced Cardiac Malformations

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zhiyong Zhao
Keyword(s):  
High Glucose ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Activin A ◽  
Brdu Incorporation ◽  
Control Group ◽  
Endocardial Cushions ◽  
Diabetic Embryopathy ◽  
Cardiac Malformations

Diabetes mellitus in pregnancy causes heart defects, especially atrioventricular septal defects (AVSDs), in infants. Manifestation of AVSDs results from dysmorphogenesis of the endocardial cushions in the embryo, which is regulated by members of the transforming growth factor (TGF) β family. Among the TGFβs, we have previously observed that the inhibin βA gene, which encodes a protein to form homodimers as activin A, is markedly downregulated by maternal diabetes. To further determine the involvement of inhibin βA and its signaling in diabetic embryopathy, the levels of inhibin βA protein and activation of its downstream transcription factors, Smad2 and Smad3, were examined using immunohistochemical, proximity ligation, and immunoblot assays, and shown to be decreased in the embryonic hearts of diabetic mice induced via intravenous injection of streptozotocin. To investigate the role of activin A in hyperglycemia-induced cardiac malformations, mouse embryos at embryonic day 9.5 (E9.5) cultured in high glucose (22 mM) were treated with activin A (50 ng/ml) for 24 hours. The treatment rescued the development of the endocardial cushions and cell proliferation (BrdU-incorporation assay) in the myocardium, similar to those in normal glucose control (8.3 mM). The role of activin A in endocardial cell migration, an important process for cellularization of the cardiac jelly, was investigated by treating E10.5 endocardial cushion explants cultured in high glucose with activin A (50 ng/ml) in a collagen matrix-based assay system. The treatment significantly increased the number of migrating cells, compared with that in high glucose-treated group, to the level in the control group. These effects were associated with restoration of the activation of Smad2/3. The results demonstrate that the activin-Smad2/3 signaling system plays an important role in cardiac malformation in diabetic embryopathy.

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