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Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic...
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Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 43376

Special Issue Editor

Prof. Dr. Roberto Ravazzolo

E-Mail Website
Guest Editor
Renata Bocciardi, Università degli Studi di Genova, Genova, Italy
Interests: human genetics; rare genetic disorders; pathophysiology of rare genetic disorders; therapeutic strategies for rare genetic disorders; fibrodysplasia ossificans progressiva

Special Issue Information

Dear Colleagues,

Research on fibrodysplasia ossificans progressiva (FOP) has achieved important results that have improved our understanding of the genetic cause, pathophysiology and clinical translation. It is important to assess the status of the scientific advancement given the variety and complexity of biological factors and processes that play a role in the disease mechanism and try to identify more and more precise targets for novel therapeutic approaches.

Prof. Roberto Ravazzolo
Guest Editor

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Keywords

  • fibrodysplasia ossificans progressiva (FOP)
  • heterotopic ossification
  • inflammatory and immunological basis of the ossification process
  • osteogenic progenitor cells
  • genomic basis of FOP phenotype
  • biomarkers
  • registry and biobank
  • therapeutic strategies
  • preclinical in vitro studies
  • preclinical in vivo studies
  • clinical trials

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

2 pages, 153 KiB  
Editorial
Editorial of Special Issue “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches”
by Roberto Ravazzolo
Biomedicines 2022, 10(1), 140; https://doi.org/10.3390/biomedicines10010140 - 10 Jan 2022
Cited by 1 | Viewed by 1242
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)

Research

Jump to: Editorial, Review

16 pages, 3045 KiB  
Article
MyD88 Is Not Required for Muscle Injury-Induced Endochondral Heterotopic Ossification in a Mouse Model of Fibrodysplasia Ossificans Progressiva
by Huili Lyu, Cody M. Elkins, Jessica L. Pierce, C. Henrique Serezani and Daniel S. Perrien
Biomedicines 2021, 9(6), 630; https://doi.org/10.3390/biomedicines9060630 - 1 Jun 2021
Cited by 8 | Viewed by 3262
Abstract
Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple [...] Read more.
Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple cell types, suggesting the importance of pathway crosstalk in EHO and FOP. Toll-like receptors (TLRs) and IL-1 receptors mediate many of the earliest injury-induced inflammatory signals largely via MyD88-dependent pathways. Thus, the hypothesis that MyD88-dependent signaling is required for EHO was tested in vitro and in vivo using global or Pdgfrα-conditional deletion of MyD88 in FOP mice. As expected, IL-1β or LPS synergistically increased Activin A (ActA)-induced phosphorylation of Smad 1/5 in fibroadipoprogenitors (FAPs) expressing Alk2R206H. However, conditional deletion of MyD88 in Pdgfrα-positive cells of FOP mice did not significantly alter the amount of muscle injury-induced EHO. Even more surprisingly, injury-induced EHO was not significantly affected by global deletion of MyD88. These studies demonstrate that MyD88-dependent signaling is dispensable for injury-induced EHO in FOP mice. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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16 pages, 1039 KiB  
Article
Activin-A Induces Early Differential Gene Expression Exclusively in Periodontal Ligament Fibroblasts from Fibrodysplasia Ossificans Progressiva Patients
by Ton Schoenmaker, Michal Mokry, Dimitra Micha, Coen Netelenbos, Nathalie Bravenboer, Marjolijn Gilijamse, E. Marelise W. Eekhoff and Teun J. de Vries
Biomedicines 2021, 9(6), 629; https://doi.org/10.3390/biomedicines9060629 - 1 Jun 2021
Cited by 9 | Viewed by 3386
Abstract
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown [...] Read more.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown that capturing Activin-A protects against heterotopic ossification in animal models, the exact underlying mechanisms at the gene expression level causing ACVR1 R206H-mediated ossifications and progression are thus far unknown. We investigated the early transcriptomic changes induced by Activin-A of healthy control and patient-derived periodontal ligament fibroblasts (PLF) isolated from extracted teeth by RNA sequencing analysis. To study early differences in response to Activin-A, periodontal ligament fibroblasts from six control teeth and from six FOP patient teeth were cultured for 24 h without and with 50 ng/mL Activin-A and analyzed with RNA sequencing. Pathway analysis on genes upregulated by Activin-A in FOP cells showed an association with pathways involved in, among others, Activin, TGFβ, and BMP signaling. Differential gene expression induced by Activin-A was exclusively seen in the FOP cells. Median centered supervised gene expression analysis showed distinct clusters of up- and downregulated genes in the FOP cultures after stimulation with Activin-A. The upregulated genes with high fold changes like SHOC2, TTC1, PAPSS2, DOCK7, and LOX are all associated with bone metabolism. Our open-ended approach to investigating the early effect of Activin-A on gene expression in control and FOP PLF shows that the molecule exclusively induces differential gene expression in FOP cells and not in control cells. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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13 pages, 2692 KiB  
Article
ALK2 Receptor Kinase Association with FKBP12.6 Is Structurally Conserved with the ALK2-FKBP12 Complex
by Eleanor Williams, Elise Riesebos, Georgina Kerr and Alex N. Bullock
Biomedicines 2021, 9(2), 129; https://doi.org/10.3390/biomedicines9020129 - 29 Jan 2021
Cited by 2 | Viewed by 3544
Abstract
The immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca2+ release. Binding of FKBP12.6 to BMP/TGF-β [...] Read more.
The immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca2+ release. Binding of FKBP12.6 to BMP/TGF-β receptors has yet to be investigated, but appears plausible given its high sequence similarity to FKBP12. Here, we found that FKBP12.6 can assemble with BMP and TGF-β-family type I receptors, but not with type II receptors. Cellular immunoprecipitation confirmed similar binding of FKBP12 and FKBP12.6 to the BMP receptor ALK2 (ACVR1), a known target of mutations in the congenital syndrome fibrodysplasia ossificans progressiva (FOP), as well as the pediatric brain tumor diffuse intrinsic pontine glioma (DIPG). SEC-MALS analyses using purified proteins indicated a direct 1:1 interaction between FKBP12.6 and the receptor’s cytoplasmic domains. The 2.17 Å structure of this ALK2-FKBP12.6 complex bound to the inhibitor dorsomorphin showed FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 extending into the FK506-binding pocket of FKBP12.6. These findings suggest a level of redundancy in FKBP-family regulation of BMP and TGF-β signaling. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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Review

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13 pages, 1882 KiB  
Review
Accumulated Knowledge of Activin Receptor-Like Kinase 2 (ALK2)/Activin A Receptor, Type 1 (ACVR1) as a Target for Human Disorders
by Takenobu Katagiri, Sho Tsukamoto and Mai Kuratani
Biomedicines 2021, 9(7), 736; https://doi.org/10.3390/biomedicines9070736 - 26 Jun 2021
Cited by 11 | Viewed by 4616
Abstract
Activin receptor-like kinase 2 (ALK2), also known as Activin A receptor type 1 (ACVR1), is a transmembrane kinase receptor for members of the transforming growth factor-β family. Wild-type ALK2/ACVR1 transduces osteogenic signaling in response to ligand binding. Fifteen years ago, a gain-of-function mutation [...] Read more.
Activin receptor-like kinase 2 (ALK2), also known as Activin A receptor type 1 (ACVR1), is a transmembrane kinase receptor for members of the transforming growth factor-β family. Wild-type ALK2/ACVR1 transduces osteogenic signaling in response to ligand binding. Fifteen years ago, a gain-of-function mutation in the ALK2/ACVR1 gene was detected in patients with the genetic disorder fibro-dysplasia ossificans progressiva, which is characterized by heterotopic ossification in soft tissues. Additional disorders, such as diffuse intrinsic pontin glioma, diffuse idiopathic skeletal hyperostosis, primary focal hyperhidrosis, and congenital heart defects, have also been found to be associated with ALK2/ACVR1. These findings further expand in vitro and in vivo model system research and promote our understanding of the molecular mechanisms of the pathogenesis and development of novel therapeutics and diagnosis for disorders associated with ALK2/ACVR1. Through aggressive efforts, some of the disorders associated with ALK2/ACVR1 will be overcome in the near future. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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22 pages, 1510 KiB  
Review
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva
by Francesc Ventura, Eleanor Williams, Makoto Ikeya, Alex N. Bullock, Peter ten Dijke, Marie-José Goumans and Gonzalo Sanchez-Duffhues
Biomedicines 2021, 9(2), 213; https://doi.org/10.3390/biomedicines9020213 - 19 Feb 2021
Cited by 9 | Viewed by 5148
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I [...] Read more.
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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15 pages, 1534 KiB  
Review
Cardiopulmonary and Neurologic Dysfunctions in Fibrodysplasia Ossificans Progressiva
by Fatima Khan, Xiaobing Yu and Edward C. Hsiao
Biomedicines 2021, 9(2), 155; https://doi.org/10.3390/biomedicines9020155 - 5 Feb 2021
Cited by 8 | Viewed by 3651
Abstract
Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare but debilitating disorder characterized by spontaneous, progressive, and irreversible heterotopic ossifications (HO) at extraskeletal sites. FOP is caused by gain-of-function mutations in the Activin receptor Ia/Activin-like kinase 2 gene (Acvr1/Alk2), with increased receptor sensitivity [...] Read more.
Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare but debilitating disorder characterized by spontaneous, progressive, and irreversible heterotopic ossifications (HO) at extraskeletal sites. FOP is caused by gain-of-function mutations in the Activin receptor Ia/Activin-like kinase 2 gene (Acvr1/Alk2), with increased receptor sensitivity to bone morphogenetic proteins (BMPs) and a neoceptor response to Activin A. There is extensive literature on the skeletal phenotypes in FOP, but a much more limited understanding of non-skeletal manifestations of this disease. Emerging evidence reveals important cardiopulmonary and neurologic dysfunctions in FOP including thoracic insufficiency syndrome, pulmonary hypertension, conduction abnormalities, neuropathic pain, and demyelination of the central nervous system (CNS). Here, we review the recent research and discuss unanswered questions regarding the cardiopulmonary and neurologic phenotypes in FOP. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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12 pages, 613 KiB  
Review
Genomic Context and Mechanisms of the ACVR1 Mutation in Fibrodysplasia Ossificans Progressiva
by Roberto Ravazzolo and Renata Bocciardi
Biomedicines 2021, 9(2), 154; https://doi.org/10.3390/biomedicines9020154 - 5 Feb 2021
Cited by 6 | Viewed by 2638
Abstract
Basic research in Fibrodysplasia Ossificans Progressiva (FOP) was carried out in the various fields involved in the disease pathophysiology and was important for designing therapeutic approaches, some of which were already developed as ongoing or planned clinical trials. Genetic research was fundamental in [...] Read more.
Basic research in Fibrodysplasia Ossificans Progressiva (FOP) was carried out in the various fields involved in the disease pathophysiology and was important for designing therapeutic approaches, some of which were already developed as ongoing or planned clinical trials. Genetic research was fundamental in identifying the FOP causative mutation, and the astonishing progress in technologies for genomic analysis, coupled to related computational methods, now make possible further research in this field. We present here a review of molecular and cellular factors which could explain why a single mutation, the R206H in the ACVR1 gene, is absolutely prevalent in FOP patients. We also address the mechanisms by which FOP expressivity could be modulated by cis-acting variants in the ACVR1 genomic region in human chromosome 2q. Finally, we also discuss the general issue of genetic modifiers in FOP. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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20 pages, 352 KiB  
Review
Genetic and Acquired Heterotopic Ossification: A Translational Tale of Mice and Men
by Serena Cappato, Riccardo Gamberale, Renata Bocciardi and Silvia Brunelli
Biomedicines 2020, 8(12), 611; https://doi.org/10.3390/biomedicines8120611 - 14 Dec 2020
Cited by 22 | Viewed by 4820
Abstract
Heterotopic ossification is defined as an aberrant formation of bone in extraskeletal soft tissue, for which both genetic and acquired conditions are known. This pathologic process may occur in many different sites such as the skin, subcutaneous tissue, skeletal muscle and fibrous tissue [...] Read more.
Heterotopic ossification is defined as an aberrant formation of bone in extraskeletal soft tissue, for which both genetic and acquired conditions are known. This pathologic process may occur in many different sites such as the skin, subcutaneous tissue, skeletal muscle and fibrous tissue adjacent to joints, ligaments, walls of blood vessels, mesentery and other. The clinical spectrum of this disorder is wide: lesions may range from small foci of ossification to massive deposits of bone throughout the body, typical of the progressive genetically determined conditions such as fibrodysplasia ossificans progressiva, to mention one of the most severe and disabling forms. The ectopic bone formation may be regarded as a failed tissue repair process in response to a variety of triggers and evolving towards bone formation through a multistage differentiation program, with several steps common to different clinical presentations and distinctive features. In this review, we aim at providing a comprehensive view of the genetic and acquired heterotopic ossification disorders by detailing the clinical and molecular features underlying the different human conditions in comparison with the corresponding, currently available mouse models. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
12 pages, 5753 KiB  
Review
Clinical Aspects and Current Therapeutic Approaches for FOP
by Hiroshi Kitoh
Biomedicines 2020, 8(9), 325; https://doi.org/10.3390/biomedicines8090325 - 2 Sep 2020
Cited by 23 | Viewed by 9078
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare heritable disorder of connective tissues characterized by progressive heterotopic ossification in various skeletal sites. It is caused by gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)/activin-like kinase 2 ( [...] Read more.
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare heritable disorder of connective tissues characterized by progressive heterotopic ossification in various skeletal sites. It is caused by gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Heterotopic ossification is usually progressive leading to severe deformities in the trunk and extremities. Early clinical diagnosis is important to prevent unnecessary iatrogenic harm or trauma. Clinicians should become aware of early detectable skeletal malformations, including great toe deformities, shortened thumb, neck stiffness associated with hypertrophy of the posterior elements of the cervical spine, multiple ossification centers in the calcaneus, and osteochondroma-like lesions of the long bones. Although there is presently no definitive medical treatment to prevent, stop or reverse heterotopic ossification in FOP, exciting advances of novel pharmacological drugs focusing on target inhibition of the activated ACVR1 receptor, including palovarotene, REGN 2477, rapamycin, and saracatinib, have developed and are currently in clinical trials. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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