BMP Signaling in Fibrodysplasia Ossificans Progressiva, a Rare Genetic Disorder of Heterotopic Ossification

2017 ◽  
pp. 327-343
Author(s):  
Eileen M. Shore ◽  
Frederick S. Kaplan
Keyword(s):  
Heterotopic Ossification ◽  
Genetic Disorder ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Rare Genetic Disorder

scholarly journals ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification

2019 ◽  
Vol 30 (1) ◽  
pp. 17-29 ◽  
Author(s):  
Julia Haupt ◽  
Alexandra Stanley ◽  
Claire M. McLeod ◽  
Brian D. Cosgrove ◽  
Andria L. Culbert ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Cell Fate ◽  
Genetic Disorder ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
In Vitro Assays ◽  
Type I ◽  
Heterotopic Bone ◽  
Mechanical Stimuli ◽  
Tissue Microenvironment

An activating bone morphogenetic proteins (BMP) type I receptor ACVR1 (ACVR1R206H) mutation enhances BMP pathway signaling and causes the rare genetic disorder of heterotopic (extraskeletal) bone formation fibrodysplasia ossificans progressiva. Heterotopic ossification frequently occurs following injury as cells aberrantly differentiate during tissue repair. Biomechanical signals from the tissue microenvironment and cellular responses to these physical cues, such as stiffness and rigidity, are important determinants of cell differentiation and are modulated by BMP signaling. We used an Acvr1R206H/+ mouse model of injury-induced heterotopic ossification to examine the fibroproliferative tissue preceding heterotopic bone and identified pathologic stiffening at this stage of repair. In response to microenvironment stiffness, in vitro assays showed that Acvr1R206H/+ cells inappropriately sense their environment, responding to soft substrates with a spread morphology similar to wild-type cells on stiff substrates and to cells undergoing osteoblastogenesis. Increased activation of RhoA and its downstream effectors demonstrated increased mechanosignaling. Nuclear localization of the pro-osteoblastic factor RUNX2 on soft and stiff substrates suggests a predisposition to this cell fate. Our data support that increased BMP signaling in Acvr1R206H/+ cells alters the tissue microenvironment and results in misinterpretation of the tissue microenvironment through altered sensitivity to mechanical stimuli that lowers the threshold for commitment to chondro/osteogenic lineages.

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

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.

Conductive Hearing Loss in Individuals with Fibrodysplasia Ossificans Progressiva

1999 ◽  
Vol 8 (1) ◽  
pp. 29-33 ◽  
Author(s):  
Charles E. Levy ◽  
Albert T. Lash ◽  
Hal B. Janoff ◽  
Frederick S. Kaplan
Keyword(s):  
Hearing Loss ◽  
Heterotopic Ossification ◽  
Congenital Malformation ◽  
Large Scale ◽  
Soft Tissues ◽  
Conductive Hearing Loss ◽  
Genetic Disorder ◽  
Postal Survey ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Conductive Hearing

Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder that is characterized by progressive heterotopic ossification of soft tissues and congenital malformation of the great toes. Although previous case studies have reported hearing loss in individuals with FOP, there have been no large-scale studies regarding the nature or cause of the hearing loss. Here, we report the findings of a two-part study. In Part I, we report the findings of a postal survey regarding hearing loss that was sent to 102 individuals with FOP. In Part II, we report the findings of on-site hearing evaluations of eight individuals with FOP. The findings of both studies indicate that individuals with FOP are at risk for hearing loss and that the type of loss is predominantly conductive in nature, similar to that seen in individuals who have otosclerosis.

scholarly journals Editorial of Special Issue “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches”

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 140
Author(s):  
Roberto Ravazzolo
Keyword(s):  
Genetic Disorder ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Special Issue ◽  
Therapeutic Approaches ◽  
Disease Mechanism ◽  
Rare Genetic Disorder ◽  
Review Articles ◽  
Novel Therapeutic

The Special Issue on “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches” has published interesting and useful review articles and original experimental articles on fibrodysplasia ossificans progressiva (FOP), a very rare genetic disorder for which much effort is being devoted to search for a cure. In this editorial, I briefly cite the essential content of all the published articles.

scholarly journals The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

2019 ◽  
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 ◽  
Morphogenetic Protein ◽  
Protein Receptors

AbstractActivin 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.Impact StatementThe non-signaling complex formed by Activin A and ACVR1 is operant in vivo and is required to temper the degree of heterotopic ossification in the genetic disorder fibrodysplasia ossificans progressiva.

scholarly journals Fibrodysplasia Ossificans Progressiva: A Case Report

2018 ◽  
Vol 16 (2) ◽  
pp. 245-247
Author(s):  
Sudeep Acharya ◽  
Sandhya Joshi ◽  
Rajib Chaulagain
Keyword(s):  
Heterotopic Ossification ◽  
Skeletal Muscles ◽  
Myositis Ossificans ◽  
Genetic Disorder ◽  
Later Life ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Permanent Disability ◽  
Radiological Features ◽  
The Individual ◽  
Fibrodysplasia Ossificans Progressive

Fibrodysplasia ossificans progressiva is a genetic disorder of the connective tissue differentiation characterized by congenital malformation of the big toes and progressive heterotopic ossification in the extra skeletal tissues like tendons, ligaments, fascia and skeletal muscles leading to permanent disability. The prevalence is one in two million people. During childhood, it may be asymptomatic but in later life, progressive stiffness of major joints renders movement of the individual impossible. Currently, there is no effective treatment for this debilitating disease. Here, we present a case of 27 year old male with clinical and radiological features of fibrodysplasia ossificans progressiva.Keywords: Fibrodysplasia ossificans progressive; heterotopic ossification; myositis ossificans; myositis ossificans progressive.

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