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 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 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 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.

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.

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

2013 ◽  
Vol 394 (6) ◽  
pp. 703-714 ◽  
Author(s):  
Takenobu Katagiri ◽  
Sho Tsukamoto
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Smad Signaling ◽  
Smad Signaling Pathway

Abstract Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor-β family. BMPs were originally identified based on their unique activity, inducing heterotopic bone formation in skeletal muscle. This unique BMP activity is transduced by specific type I and type II transmembrane kinase receptors. Among the downstream pathways activated by these receptors, the Smad1/5/8 transcription factors appear to play critical roles in BMP activity. Smad1/5/8 transcription factors are phosphorylated at the C-terminal SVS motif by BMP type I receptors and then induce the transcription of early BMP-responsive genes by binding to conserved sequences in their enhancer regions. The linker regions of Smad1/5/8 contain multiple kinase phosphorylation sites, and phosphorylation and dephosphorylation of these sites regulate the transcriptional activity of Smad proteins. Gain-of-function mutations in one BMP type I receptor have been identified in patients with fibrodysplasia ossificans progressiva, a rare genetic disorder that is characterized by progressive heterotopic bone formation in the skeletal muscle. The mutant receptors activate the Smad signaling pathway even in the absence of BMPs, therefore novel inhibitors for the BMP receptor – Smad axis are being developed to prevent heterotopic bone formation in fibrodysplasia ossificans progressiva. Taken together, the data in the literature show that the BMP type I receptor – Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.

scholarly journals Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva

2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Alexandra Stanley ◽  
Elisia D. Tichy ◽  
Jacob Kocan ◽  
Douglas W. Roberts ◽  
Eileen M. Shore ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Skeletal Muscles ◽  
Skeletal Muscle Regeneration ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Differentiation Potential ◽  
Resident Stem Cells

AbstractFibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which extraskeletal (heterotopic) bone forms within tissues such as skeletal muscles, often in response to injury. Mutations in the BMP type I receptor ACVR1/ALK2 cause FOP by increasing BMP pathway signaling. In contrast to the growing understanding of the inappropriate formation of bone tissue within the muscle in FOP, much is still unknown about the regenerative capacity of adult diseased muscles. Utilizing an inducible ACVR1R206H knock-in mouse, we found that injured Acvr1R206H/+ skeletal muscle tissue regenerates poorly. We demonstrated that while two resident stem cell populations, muscle stem cells (MuSCs) and fibro/adipogenic progenitors (FAPs), have similar proliferation rates after injury, the differentiation potential of mutant MuSCs is compromised. Although MuSC-specific deletion of the ACVR1R206H mutation does not alter the regenerative potential of skeletal muscles in vivo, Acvr1R206H/+ MuSCs form underdeveloped fibers that fail to fuse in vitro. We further determined that FAPs from Acvr1R206H/+ mice repress the MuSC-mediated formation of Acvr1R206H/+ myotubes in vitro. These results identify a previously unrecognized role for ACVR1R206H in myogenesis in FOP, via improper interaction of tissue-resident stem cells during skeletal muscle regeneration.

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 Differential Vascularity in Genetic and Nonhereditary Heterotopic Ossification

2019 ◽  
Vol 27 (8) ◽  
pp. 859-867 ◽  
Author(s):  
Alisha D. Ware ◽  
Niambi Brewer ◽  
Carolyn Meyers ◽  
Carol Morris ◽  
Edward McCarthy ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Heterotopic Ossification ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone ◽  
Common Complication ◽  
Histomorphometric Analysis ◽  
Temporal Dynamic ◽  
Dynamic Changes ◽  
Vascular Patterning ◽  
Progressive Osseous Heteroplasia

Introduction. Nonhereditary heterotopic ossification (NHO) is a common complication of trauma. Progressive osseous heteroplasia (POH) and fibrodysplasia ossificans progressiva (FOP) are rare genetic causes of heterotopic bone. In this article, we detail the vascular patterning associated with genetic versus NHO. Methods. Vascular histomorphometric analysis was performed on patient samples from POH, FOP, and NHO. Endpoints for analysis included blood vessel (BV) number, area, density, size, and wall thickness. Results. Results demonstrated conserved temporal dynamic changes in vascularity across all heterotopic ossification lesions. Immature areas had the highest BV number, while the more mature foci had the highest BV area. Most vascular parameters were significantly increased in genetic as compared with NHO. Discussion. In sum, both genetic and NHO show temporospatial variation in vascularity. These findings suggest that angiogenic pathways are potential therapeutic targets in both genetic and nonhereditary forms of heterotopic ossification.

scholarly journals Post-COVID-19 exacerbation of fibrodysplasia ossificans progressiva with multiple flare-ups and extensive heterotopic ossification in a 45-year-old female patient

2021 ◽  
Author(s):  
Lovorka Grgurevic ◽  
Rudjer Novak ◽  
Stela Hrkac ◽  
Grgur Salai ◽  
Simeon Grazio
Keyword(s):  
Heterotopic Ossification ◽  
Female Patient ◽  
Soft Tissues ◽  
Hereditary Disease ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Cytokine Analysis ◽  
Viral Illness ◽  
First Time

AbstractFibrodyplasia ossificans progressiva (FOP) is a rare hereditary disease, which has a variable course characterized by occasional flare-ups of heterotopic ossification (HO) in soft tissues that are followed by swelling, stiffness, pain and warmth. Here, we report for the first time a case of a 45-year-old female patient with known FOP recovering from COVID-19 with disease progression potentially linked with the viral illness. In December 2020 the patient contracted a mild form of COVID-19 infection without need for hospital admission. Since January 2021, the patient felt unwell, with occasional abdominal pain which progressively intensified. In March 2021 she presented with new onset of HO, complaining of pain, swelling and thickening sensation in the lower abdomen and left part of the neck. Computerized tomography (CT) and cytokine analysis were performed. CT scan revealed new heterotopic bone formation in multiple soft tissue areas of the neck indicating clear radiological progression. Radiotherapy, which has proven to be an efficient tool to control HO in this patient, was not able to halt HO formation after COVID-19 infection. Cytokine analysis of a plasma sample obtained during a flare-up after COVID-19 infection showed a significantly elevated pro-inflammatory cytokines compared to a flare-up panel prior to infection. Of the 23 analyzed levels of cytokines, a staggering number of 21 were above normal levels. This case is the first confirmation of uncontrolled post-COVID-19 effects in a FOP patient, which manifested with flare-ups followed by progressive HO, possibly caused by a thus far, never described form of post-COVID syndrome.

Sign in / Sign up

Export Citation Format

Share Document