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Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 10023

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Special Issue Editors

Dr. Frederick S. Kaplan

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Guest Editor

Department of Orthopaedic Surgery and Medicine, The Center for Research in FOP & Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: fibrodysplasia ossificans progressiva (FOP); progressive osseous heteroplasia (POH); heterotopic ossification; drug development

Dr. Robert J. Pignolo

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Guest Editor

Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Interests: fibrodysplasia ossificans progressiva (FOP); heterotopic ossification; aging; metabolic bone disease; cell senescence; drug development

Special Issue Information

Dear Colleagues,

In the introduction to his 1970 textbook Biochemistry, Albert Lehninger wrote that “Living things are composed of lifeless molecules.” More than fifty years and worlds of insight later, we know more about those biomolecules, the genes that encode them, and the pathophysiology and personal devastation caused by errors in these biomolecules. There may be no greater illustration of this than fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder in which a second skeleton of heterotopic bone is formed.

The discovery of the FOP gene (the mutated ACVR1 bone morphogenetic protein (BMP) type I receptor) heralded the emergence of a new grammar for drug discovery in FOP and an explosion of interest in the well-defined and evolutionarily conserved BMP signaling pathway.

Discovery of the FOP gene enabled the development of animal models of FOP, which have been instrumental in testing novel therapeutics for druggable targets. Animal models have validated the dysregulated BMP signaling pathway, the pathophysiology of heterotopic ossification (HO), and the progenitor cells responsible for HO in FOP.

Dramatic basic scientific discoveries, coupled with a comprehensive understanding of the natural history of FOP, have fueled the advent of clinical trials—an extraordinary achievement for an ultra-rare condition that has existed in the backwaters of medicine for over three centuries.

This Special Issue of Biomolecules, “Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies”, aims to explore the connection between the molecular mechanisms and therapeutic strategies that are currently being explored in FOP, and by extension, in more common disorders of HO that plague millions of individuals worldwide.

We welcome original research articles and reviews. Research areas may include (but are not limited to):

The molecular genetics of FOP;
The dysregulated bone morphogenetic protein (BMP) pathway in FOP;
Molecular crosstalk in seminal pathways leading to HO;
Senolytic pathways in FOP;
Immunological aspects of FOP;
Progenitor cells in FOP;
Developmental physiology of FOP;
FOP: clues from Drosophila;
FOP: molecular lessons from Zebrafish;
Mouse models of FOP;
Molecular biomechanics of FOP;
Molecular imaging in FOP;
Pharmaceutical perspectives in FOP;
Gene therapy in FOP;
What FOP can teach us about non-genetic forms of HO.

We look forward to receiving your contributions.

Dr. Frederick S. Kaplan
Dr. Robert J. Pignolo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

fibrodysplasia ossificans progressiva
bone morphogenetic protein (BMP)
signaling pathway
ACVR1
fibro/adipogenic progenitor cells (FAPs)
heterotopic ossification

Published Papers (7 papers)

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Research

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13 pages, 4011 KiB

Open AccessArticle

Hedgehog Signaling Controls Chondrogenesis and Ectopic Bone Formation via the Yap-Ihh Axis

by Qian Cong and Yingzi Yang

Biomolecules 2024, 14(3), 347; https://doi.org/10.3390/biom14030347 - 14 Mar 2024

Viewed by 837

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of HO. Here we find that Hh signaling activation is required for the aberrant ectopic bone formation in FOP. We show that the expression of Indian hedgehog (Ihh), a Hh ligand, as well as downstream Hh signaling, was increased in ectopic bone lesions in Acvr1^R206H; ScxCre mice. Pharmacological treatment with an Ihh-neutralizing monoclonal antibody dramatically reduced chondrogenesis and ectopic bone formation. Moreover, we find that the activation of Yap in the FOP mouse model and the genetic deletion of Yap halted ectopic bone formation and decreased Ihh expression. Our mechanistic studies showed that Yap and Smad1 directly bind to the Ihh promoter and coordinate to induce chondrogenesis by promoting Ihh expression. Therefore, the Yap activation in FOP lesions promoted ectopic bone formation and expansion in both cell-autonomous and non-cell-autonomous manners. These results uncovered the crucial role of the Yap-Ihh axis in FOP pathogenesis, suggesting the inhibition of Ihh or Yap as a potential therapeutic strategy to prevent and reduce HO. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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20 pages, 4905 KiB

Open AccessArticle

Sex as a Critical Variable in Basic and Pre-Clinical Studies of Fibrodysplasia Ossificans Progressiva

by Lorraine N. Burdick, Amanda H. DelVichio, L. Russell Hanson, Brenden B. Griffith, Keith R. Bouchard, Jeffrey W. Hunter and David J. Goldhamer

Biomolecules 2024, 14(2), 177; https://doi.org/10.3390/biom14020177 - 01 Feb 2024

Viewed by 1514

Abstract

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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17 pages, 3685 KiB

Open AccessEditor’s ChoiceArticle

AAV-Mediated Targeting of the Activin A-ACVR1^R206H Signaling in Fibrodysplasia Ossificans Progressiva

by Yeon-Suk Yang, Chujiao Lin, Hong Ma, Jun Xie, Frederick S. Kaplan, Guangping Gao and Jae-Hyuck Shim

Biomolecules 2023, 13(9), 1364; https://doi.org/10.3390/biom13091364 - 08 Sep 2023

Cited by 4 | Viewed by 1764

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1^R206H (Acvr1^R206H/+) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1^opt) and artificial miRNAs targeting Activin A and its receptor ACVR1^R206H ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of Acvr1^R206H/+ skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in Acvr1^R206H/+ mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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21 pages, 4354 KiB

Open AccessFeature PaperArticle

Polypeptide Substrate Accessibility Hypothesis: Gain-of-Function R206H Mutation Allosterically Affects Activin Receptor-like Protein Kinase Activity

by Jay C. Groppe, Guorong Lu, Mary R. Tandang-Silvas, Anupama Pathi, Shruti Konda, Jingfeng Wu, Viet Q. Le, Andria L. Culbert, Eileen M. Shore, Kristi A. Wharton and Frederick S. Kaplan

Biomolecules 2023, 13(7), 1129; https://doi.org/10.3390/biom13071129 - 14 Jul 2023

Cited by 2 | Viewed by 1336

Abstract

Although structurally similar to type II counterparts, type I or activin receptor-like kinases (ALKs) are set apart by a metastable helix–loop–helix (HLH) element preceding the protein kinase domain that, according to a longstanding paradigm, serves passive albeit critical roles as an inhibitor-to-substrate-binding switch. A single recurrent mutation in the codon of the penultimate residue, directly adjacent the position of a constitutively activating substitution, causes milder activation of ACVR1/ALK2 leading to sporadic heterotopic bone deposition in patients presenting with fibrodysplasia ossificans progressiva, or FOP. To determine the protein structural–functional basis for the gain of function, R206H mutant, Q207D (aspartate-substituted caALK2) and HLH subdomain-truncated (208 Ntrunc) forms were compared to one another and the wild-type enzyme through in vitro kinase and protein–protein interaction analyses that were complemented by signaling read-out (p-Smad) in primary mouse embryonic fibroblasts and Drosophila S2 cells. Contrary to the paradigm, the HLH subdomain actively suppressed the phosphotransferase activity of the enzyme, even in the absence of FKBP12. Unexpectedly, perturbation of the HLH subdomain elevated kinase activity at a distance, i.e., allosterically, at the ATP-binding and polypeptide-interacting active site cleft. Accessibility to polypeptide substrate (BMP Smad C-terminal tails) due to allosterically altered conformations of type I active sites within heterohexameric cytoplasmic signaling complexes—assembled noncanonically by activin-type II receptors extracellularly—is hypothesized to produce a gain of function of the R206H mutant protein responsible for episodic heterotopic ossification in FOP. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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Review

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17 pages, 1019 KiB

Open AccessReview

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

by Anastasia Diolintzi, Mst Shaela Pervin and Edward C. Hsiao

Biomolecules 2024, 14(3), 357; https://doi.org/10.3390/biom14030357 - 16 Mar 2024

Viewed by 1131

Abstract

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP. Future perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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27 pages, 1819 KiB

Open AccessReview

Intersections of Fibrodysplasia Ossificans Progressiva and Traumatic Heterotopic Ossification

by Conan Juan, Alec C. Bancroft, Ji Hae Choi, Johanna H. Nunez, Chase A. Pagani, Yen-Sheng Lin, Edward C. Hsiao and Benjamin Levi

Biomolecules 2024, 14(3), 349; https://doi.org/10.3390/biom14030349 - 14 Mar 2024

Viewed by 911

Abstract

Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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14 pages, 903 KiB

Open AccessReview

How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva

by Dushyanth Srinivasan, Martin Arostegui, Erich J. Goebel, Kaitlin N. Hart, Senem Aykul, John B. Lees-Shepard, Vincent Idone, Sarah J. Hatsell and Aris N. Economides

Biomolecules 2024, 14(1), 101; https://doi.org/10.3390/biom14010101 - 12 Jan 2024

Viewed by 1677

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1^FOP) and/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1^FOP by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1^FOP and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP’s pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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