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 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 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 Identification of the Identical Human Mutation in ACVR1 in 2 Cats With Fibrodysplasia Ossificans Progressiva

2019 ◽  
Vol 56 (4) ◽  
pp. 614-618 ◽  
Author(s):  
Margret L. Casal ◽  
Julie B. Engiles ◽  
Maja Zakošek Pipan ◽  
Asaf Berkowitz ◽  
Yael Porat-Mosenco ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterozygous Mutation ◽  
Type I ◽  
Heterotopic Bone ◽  
Intact Male ◽  
Shoulder Joints ◽  
Pelvic Limb ◽  
Human Mutation ◽  
Reduced Mobility

Two domestic shorthair cats, 1 intact female and 1 intact male, presented with progressive limb lameness and digital deformities at 4 and 6 months of age. Stiffness and swelling of the distal thoracic and pelvic limb joints progressed to involve hip and shoulder joints, resulting in reduced mobility. Radiographs in both cats and computed tomography of the male cat revealed ankylosing, polyarticular deposits of extracortical heterotopic bone spanning multiple axial and appendicular joints, extending into adjacent musculotendinous tissues. All findings supported fibrodysplasia ossificans progressiva (FOP), a disorder characterized by toe malformations and progressive heterotopic ossification in humans. In both cats, molecular analyses revealed the same heterozygous mutation in the activin A receptor type I ( ACVR1) gene that occurs in humans with FOP. Several reports of heterotopic ossification in cats exist, but this is the first one to identify clinical FOP in 2 cats with the identical mutation that occurs in >95% of humans with FOP.

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.

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 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 Over-expression of wild-type ACVR1 in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification

2021 ◽  
Author(s):  
Masakazu Yamamoto ◽  
Sean J Stoessel ◽  
Shoko Yamamoto ◽  
David J Goldhamer
Keyword(s):  
Heterotopic Ossification ◽  
Cultured Cells ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Clinical Aspects ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Wild Type ◽  
Over Expression ◽  
Severity Of Injury ◽  
Perinatal Lethality

Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally over-express human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H/+ mice was rescued by constitutive ACVR1 over-expression and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive over-expression of ACVR1 also provided protection from spontaneous HO, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 over-expression functions cell-autonomously by reducing osteogenic signaling in response to activin A. Manipulating the stoichiometry of FOP-causing and wild-type ACVR1 receptors may provide the foundation for novel therapeutic strategies to treat this devastating disease.

scholarly journals Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

eLife ◽  
2020 ◽  
Vol 9 ◽  
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 ◽  
Bmp Receptors

Activin 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.

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