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 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 Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Robyn S Allen ◽  
Benjamin Tajer ◽  
Eileen M Shore ◽  
Mary C Mullins
Keyword(s):  
Skeletal Development ◽  
Genetic Disorder ◽  
Bmp Signaling ◽  
Cell Surface Receptor ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Activating Mutations ◽  
Pathway Activation ◽  
Surface Receptor ◽  
Human Genetic Disorder

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by altered skeletal development and extraskeletal ossification. All cases of FOP are caused by activating mutations in the type I BMP/TGFβ cell surface receptor ACVR1, which over-activates signaling through phospho-Smad1/5 (pSmad1/5). To investigate the mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used zebrafish embryonic dorsoventral (DV) patterning as an assay for BMP signaling. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H has the ability to respond to both Bmp7 and Activin A ligands. Additionally, BMPR1, a type I BMP receptor normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent signaling pathway activation and ligand-responsive signaling hyperactivation by ACVR1-R206H. These results demonstrate that FOP-ACVR1 is not constrained by the same receptor/ligand partner requirements as WT-ACVR1.

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 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 Mutant Activin-Like Kinase 2 in Fibrodysplasia Ossificans Progressiva are Activated via T203 by BMP Type II Receptors

2015 ◽  
Vol 29 (1) ◽  
pp. 140-152 ◽  
Author(s):  
Mai Fujimoto ◽  
Satoshi Ohte ◽  
Kenji Osawa ◽  
Arei Miyamoto ◽  
Sho Tsukamoto ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Soft Tissues ◽  
Genetic Disorder ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Type Ii ◽  
Activin Receptor ◽  
Bmp Receptors

Abstract Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic ossification in soft tissues, such as the skeletal muscles. FOP has been shown to be caused by gain-of-function mutations in activin receptor-like kinase (ALK)-2, which is a type I receptor for bone morphogenetic proteins (BMPs). In the present study, we examined the molecular mechanisms that underlie the activation of intracellular signaling by mutant ALK2. Mutant ALK2 from FOP patients enhanced the activation of intracellular signaling by type II BMP receptors, such as BMPR-II and activin receptor, type II B, whereas that from heart disease patients did not. This enhancement was dependent on the kinase activity of the type II receptors. Substitution mutations at all nine serine and threonine residues in the ALK2 glycine- and serine-rich domain simultaneously inhibited this enhancement by the type II receptors. Of the nine serine and threonine residues in ALK2, T203 was found to be critical for the enhancement by type II receptors. The T203 residue was conserved in all of the BMP type I receptors, and these residues were essential for intracellular signal transduction in response to ligand stimulation. The phosphorylation levels of the mutant ALK2 related to FOP were higher than those of wild-type ALK2 and were further increased by the presence of type II receptors. The phosphorylation levels of ALK2 were greatly reduced in mutants carrying a mutation at T203, even in the presence of type II receptors. These findings suggest that the mutant ALK2 related to FOP is enhanced by BMP type II receptors via the T203-regulated phosphorylation of ALK2.

scholarly journals Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

2020 ◽  
Author(s):  
Eleanor Williams ◽  
Jana Bagarova ◽  
Georgina Kerr ◽  
Dong-Dong Xia ◽  
Elsie S. Place ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Soft Tissues ◽  
Kinase Inhibitor ◽  
Tissue Injury ◽  
Soft Tissue Injury ◽  
Biologically Active ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone ◽  
Transgenic Mouse Line ◽  
Clinical Candidate

AbstractCurrently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues due to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2/ACVR1. From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2 compared with other receptors of the BMP/TGFβ signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D transgenic mouse line, which provides a model of heterotopic ossification, as well as an inducible ACVR1R206H knock-in, which serves as a genetically and physiologically faithful model of FOP. In both models, saracatinib was well tolerated and potently inhibited the development of heterotopic ossification even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in the treatment of FOP, offering an accelerated path to clinical proof of efficacy studies and potentially significant benefits to individuals with this devastating condition.

XBMPRII, a novel Xenopus type II receptor mediating BMP signaling in embryonic tissues

Development ◽  
1998 ◽  
Vol 125 (3) ◽  
pp. 431-442 ◽  
Author(s):  
A. Frisch ◽  
C.V. Wright
Keyword(s):  
Cell Fate ◽  
Organizer Region ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Mesoderm Induction ◽  
Type I ◽  
Type Ii ◽  
Common Component ◽  
Activin Signaling

Bone Morphogenetic Proteins (BMPs) are potent regulators of embryonic cell fate that are presumed to initiate signal transduction in recipient cells through multimeric, transmembrane, serine/threonine kinase complexes made up of type I and type II receptors. BMPRII was identified previously in mammals as the only type II receptor that binds BMPs, but not activin or TGFbeta, in vitro. We report the cloning and functional analysis in vivo of its Xenopus homolog, XBMPRII. XBMPRII is expressed maternally and zygotically in an initially unrestricted manner. Strikingly, XBMPRII transcripts then become restricted to the mesodermal precursors during gastrulation. Expression is lower in the dorsal organizer region, potentially providing a mechanism to suppress the actions of BMP4 on dorsally fated tissues. Similar to the results seen for a truncated type I BMP receptor (tBR), a dominant-negative form of XBMPRII (tBRII) can dorsalize ventral mesoderm, induce extensive secondary body axes, block mesoderm induction by BMP4 and directly neuralize ectoderm, strongly suggesting that XBMPRII mediates BMP signals in vivo. However, although both tBRII and tBR can induce partial secondary axes, marker analysis shows that tBRII-induced axes are more anteriorly extended. Additionally, coinjection of tBRII and tBR synergistically increases the incidence of secondary axis formation. A truncated activin type II receptor (deltaXAR1) is known to block both activin and BMP signaling in vivo. Here we show that such crossreactivity does not occur for tBRII, in that it does not affect activin signaling. Furthermore, our studies indicate that the full-length activin type II receptor (XAR1) overcomes a block in BMP4 signaling imposed by tBRII, implicating XAR1 as a common component of BMP and activin signaling pathways in vivo. These data implicate XBMPRII as a type II receptor with high selectivity for BMP signaling, and therefore as a critical mediator of the effects of BMPs as mesodermal patterning agents and suppressors of neural fate during embryogenesis.

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