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

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.

scholarly journals Intraperitoneal administration of activin A promotes development of endometriotic lesions in a mouse model of endometriosis

2019 ◽  
Vol 66 (1.2) ◽  
pp. 123-127 ◽  
Author(s):  
Kana Kasai ◽  
Takeshi Kato ◽  
Yuri Kadota ◽  
Otgontsetseg Erdenebayar ◽  
Kaoru Keyama ◽  
...  
Keyword(s):  
Mouse Model ◽  
Intraperitoneal Administration ◽  
Activin A

scholarly journals Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva

2018 ◽  
Vol 33 (2) ◽  
pp. 269-282 ◽  
Author(s):  
Michael R Convente ◽  
Salin A Chakkalakal ◽  
EnJun Yang ◽  
Robert J Caron ◽  
Deyu Zhang ◽  
...  
Keyword(s):  
Mast Cells ◽  
Mouse Model ◽  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva

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 Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

2015 ◽  
Vol 135 (1) ◽  
pp. 212-221 ◽  
Author(s):  
Magdalena Heinz ◽  
Heide Leb Niederleithner ◽  
Emmi Puujalka ◽  
Ana Soler-Cardona ◽  
Michael Grusch ◽  
...  
Keyword(s):  
Mouse Model ◽  
Activin A

Inhibition of activin A signalling in a mouse model of pre-eclampsia

Placenta ◽  
2015 ◽  
Vol 36 (8) ◽  
pp. 926-931 ◽  
Author(s):  
R. Lim ◽  
S. Adhikari ◽  
S. Gurusinghe ◽  
B. Leaw ◽  
R. Acharya ◽  
...  
Keyword(s):  
Mouse Model ◽  
Activin A

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 Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
John B Lees-Shepard ◽  
Sarah-Anne E Nicholas ◽  
Sean J Stoessel ◽  
Parvathi M Devarakonda ◽  
Michael J Schneider ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Bone Growth ◽  
Genetic Disorder ◽  
Activin A ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Skeletal Maturation ◽  
Long Bone ◽  
Synovial Joint ◽  
Live Animal

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs’ skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.

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