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 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 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

Wrist Arthrodesis Following Ulnar Bar Excision in Fibrodysplasia Ossificans Progressiva

2000 ◽  
Vol 25 (2) ◽  
pp. 223-224 ◽  
Author(s):  
L. CORFIELD ◽  
R. HAMPTON ◽  
C. J. MCCULLOUGH
Keyword(s):  
Skeletal Muscle ◽  
Functional Result ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Surgical Trauma ◽  
Heterotopic Bone ◽  
Connective Tissues ◽  
Wrist Arthrodesis ◽  
Good Functional Result ◽  
Progressive Development ◽  
Hand Disability

Fibrodysplasia ossificans progressiva is a rare disorder characterized by the progressive development of heterotopic bone in the connective tissues of skeletal muscle, ligaments and tendons. Surgical trauma is one of the most potent stimuli for ossification and surgical treatment is generally considered to be contraindicated in this condition. We report a good functional result in a patient with severe hand disability secondary to an ulna-carpal bar in fibrodysplasia ossificans progressiva.

scholarly journals Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

2020 ◽  
Author(s):  
Eleanor Williams ◽  
Jana Bagarova ◽  
Georgina Kerr ◽  
Dong-Dong Xia ◽  
Elsie S. Place ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Soft Tissues ◽  
Kinase Inhibitor ◽  
Tissue Injury ◽  
Soft Tissue Injury ◽  
Biologically Active ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone ◽  
Transgenic Mouse Line ◽  
Clinical Candidate

AbstractCurrently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues due to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2/ACVR1. From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2 compared with other receptors of the BMP/TGFβ signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D transgenic mouse line, which provides a model of heterotopic ossification, as well as an inducible ACVR1R206H knock-in, which serves as a genetically and physiologically faithful model of FOP. In both models, saracatinib was well tolerated and potently inhibited the development of heterotopic ossification even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in the treatment of FOP, offering an accelerated path to clinical proof of efficacy studies and potentially significant benefits to individuals with this devastating condition.

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