scholarly journals An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro/adipogenic progenitors in fibrodysplasia ossificans progressiva mice

2021 ◽  
Author(s):  
John B Lees-Shepard ◽  
Sean J Stoessel ◽  
Julian Chandler ◽  
Keith Bouchard ◽  
Patricia Bento ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Mouse Models ◽  
Soft Tissues ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Morphogenetic Protein ◽  
Overexpressing Cell ◽  
Pathological Consequence

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP is caused by dominantly acting mutations in the bone morphogenetic protein (BMP) type I receptor, ACVR1 (also known as ALK2), the most prevalent of which is an arginine to histidine substitution [ACVR1(R206H)] in the glycine-serine rich intracellular domain of the receptor. A fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in responsive progenitors, which drives skeletogenic commitment and HO. With the clear targets of activin A and ACVR1 identified, development of antibody therapeutics to prevent ligand-receptor interactions is an interventional approach currently being explored. Here, we developed a monoclonal blocking antibody (JAB0505) to the extracellular domain of ACVR1 and tested its ability to inhibit HO in established FOP mouse models. JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines. Strikingly, however, JAB0505 treatment markedly exacerbated injury-induced HO in two independent FOP mouse models in which ACVR1(R206H) was either broadly expressed, or more selectively expressed in fibro/adipogenic progenitors (FAPs). JAB0505 drove HO even under conditions of activin A inhibition, indicating that JAB0505 has receptor agonist activity. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. In addition, skeletogenic differentiation was both delayed and prolonged, and this was accompanied by dysregulation of FAP population growth. Collectively, alterations in the growth and differentiative properties of FAPs and FAP-derived skeletal cells are implicated in the aggravated HO phenotype. These data raise serious safety and efficacy concerns for the use of anti-ACVR1 antibodies to treat FOP patients.

scholarly journals Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling

2020 ◽  
Vol 21 (18) ◽  
pp. 6498
Author(s):  
Chen Xie ◽  
Wenjuan Jiang ◽  
Jerome J. Lacroix ◽  
Yun Luo ◽  
Jijun Hao
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanism ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Type Ii ◽  
Signaling Complex ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Activins transduce the TGF-β pathway through a heteromeric signaling complex consisting of type I and type II receptors, and activins also inhibit bone morphogenetic protein (BMP) signaling mediated by type I receptor ALK2. Recent studies indicated that activin A cross-activates the BMP pathway through ALK2R206H, a mutation associated with Fibrodysplasia Ossificans Progressiva (FOP). How activin A inhibits ALK2WT-mediated BMP signaling but activates ALK2R206H-mediated BMP signaling is not well understood, and here we offer some insights into its molecular mechanism. We first demonstrated that among four BMP type I receptors, ALK2 is the only subtype able to mediate the activin A-induced BMP signaling upon the dissociation of FKBP12. We further showed that BMP4 does not cross-signal TGF-β pathway upon FKBP12 inhibition. In addition, although the roles of type II receptors in the ligand-independent BMP signaling activated by FOP-associated mutant ALK2 have been reported, their roles in activin A-induced BMP signaling remains unclear. We demonstrated in this study that the known type II BMP receptors contribute to activin A-induced BMP signaling through their kinase activity. Together, the current study provided important mechanistic insights at the molecular level into further understanding physiological and pathophysiological BMP signaling.

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 Clinical Aspects and Current Therapeutic Approaches for FOP

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 325
Author(s):  
Hiroshi Kitoh
Keyword(s):  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Clinical Aspects ◽  
Type I ◽  
Gene Encoding ◽  
Neck Stiffness ◽  
Skeletal Malformations ◽  
Morphogenetic Protein ◽  
Heritable Disorder ◽  
Ossification Centers

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.

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.

Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva

2008 ◽  
Vol 1 (1) ◽  
pp. 91-94 ◽  
Author(s):  
Kareem A. Zaghloul ◽  
Gregory G. Heuer ◽  
Marta D. Guttenberg ◽  
Eileen M. Shore ◽  
Frederick S. Kaplan ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Heterotopic Ossification ◽  
Lumbar Puncture ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Autosomal Dominant Disorder ◽  
Tissue Mass ◽  
Morphogenetic Protein ◽  
Activating Mutation ◽  
Iatrogenic Harm

✓ Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant disorder characterized by congenital malformation of the great toes and episodes of soft tissue swelling that lead to progressive heterotopic ossification. The genetic cause of FOP was recently discovered to be a recurrent missense activating mutation in the activin A type I receptor, a bone morphogenetic protein type I receptor in all classically affected individuals worldwide. The authors present a child with the classic features of previously undiagnosed FOP who developed a paraspinal soft-tissue mass after a lumbar puncture for a fever workup. Excision of the mass resulted in a massive inflammatory response leading to progression of heterotopic ossification. Awareness of the classic clinical features of FOP prior to the appearance of heterotopic ossification can prompt early clinical diagnosis and confirmation through genetic testing, thus avoiding interventions that lead to irreversible iatrogenic harm.

scholarly journals Fibrodysplasia Ossificans Progressiva: A Challenging Diagnosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1187
Author(s):  
Daniele De Brasi ◽  
Francesca Orlando ◽  
Valeria Gaeta ◽  
Maria De Liso ◽  
Fabio Acquaviva ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Hallux Valgus ◽  
Axial Skeleton ◽  
Typical Feature ◽  
Fibrodysplasia Ossificans Progressiva ◽  
High Dose ◽  
Type I ◽  
Activating Mutations ◽  
Morphogenetic Protein ◽  
Essential Interventions

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic condition characterized by extraskeletal bone formation. Most of the musculoskeletal characteristics of FOP are related to dysregulated chondrogenesis, with heterotopic ossification being the most typical feature. Activating mutations of activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the skeletal and nonskeletal features. The clinical phenotype is always consistent, with congenital bilateral hallux valgus malformation and early-onset heterotopic ossification occurring spontaneously or, more frequently, precipitated by trauma. Painful, recurrent soft-tissue swellings (flare-ups) precede localized heterotopic ossification that can occur at any location, typically affecting regions near the axial skeleton and later progressing to the appendicular bones. A diagnosis of FOP is suspected in a proband presenting with hallux valgus malformation, heterotopic ossification, and confirmed by the identification of a heterozygous pathogenic variant in the ACVR1/ALK2 gene. Avoiding unnecessary surgical procedures, prescribing prophylactic corticosteroids, preventing falls, and using protective headgear represent essential interventions for care management. Different classes of medications to contain acute inflammation flare-ups have been proposed, with high dose corticosteroids and nonsteroidal anti-inflammatory drugs usually utilized. Here, we report on two FOP patients, with typical clinical features summarizing the principal aspects of FOP, and we aim to provide comprehensive information outlining some unusual findings, possibly contributing to FOP’s definition and management.

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 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 Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation

2021 ◽  
Vol 14 (665) ◽  
pp. eaaz9368
Author(s):  
Jingwen Yang ◽  
Megumi Kitami ◽  
Haichun Pan ◽  
Masako Toda Nakamura ◽  
Honghao Zhang ◽  
...  
Keyword(s):  
Neural Crest ◽  
Neural Crest Cells ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Cranial Neural Crest ◽  
Connective Tissues ◽  
Multipotent Stem Cells ◽  
Morphogenetic Protein ◽  
Cranial Neural Crest Cells

Cranial neural crest cells (CNCCs) are a population of multipotent stem cells that give rise to craniofacial bone and cartilage during development. Bone morphogenetic protein (BMP) signaling and autophagy have been individually implicated in stem cell homeostasis. Mutations that cause constitutive activation of the BMP type I receptor ACVR1 cause the congenital disorder fibrodysplasia ossificans progressiva (FOP), which is characterized by ectopic cartilage and bone in connective tissues in the trunk and sometimes includes ectopic craniofacial bones. Here, we showed that enhanced BMP signaling through the constitutively activated ACVR1 (ca-ACVR1) in CNCCs in mice induced ectopic cartilage formation in the craniofacial region through an autophagy-dependent mechanism. Enhanced BMP signaling suppressed autophagy by activating mTORC1, thus blocking the autophagic degradation of β-catenin, which, in turn, caused CNCCs to adopt a chondrogenic identity. Transient blockade of mTORC1, reactivation of autophagy, or suppression of Wnt–β-catenin signaling reduced ectopic cartilages in ca-Acvr1 mutants. Our results suggest that BMP signaling and autophagy coordinately regulate β-catenin activity to direct the fate of CNCCs during craniofacial development. These findings may also explain why some patients with FOP develop ectopic bones through endochondral ossification in craniofacial regions.

scholarly journals Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

2015 ◽  
Vol 112 (50) ◽  
pp. 15438-15443 ◽  
Author(s):  
Kyosuke Hino ◽  
Makoto Ikeya ◽  
Kazuhiko Horigome ◽  
Yoshihisa Matsumoto ◽  
Hayao Ebise ◽  
...  
Keyword(s):  
Bone Formation ◽  
Endochondral Ossification ◽  
Point Mutations ◽  
Activin A ◽  
Bmp Signaling ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Induced Pluripotent

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.

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