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Disease Models & Mechanisms Nov 2012Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of connective tissue metamorphosis. It is characterized by malformation of... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of connective tissue metamorphosis. It is characterized by malformation of the great (big) toes during embryonic skeletal development and by progressive heterotopic endochondral ossification (HEO) postnatally, which leads to the formation of a second skeleton of heterotopic bone. Individuals with these classic clinical features of FOP have the identical heterozygous activating mutation (c.617G>A; R206H) in the gene encoding ACVR1 (also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Disease activity caused by this ACVR1 mutation also depends on altered cell and tissue physiology that can be best understood in the context of a high-fidelity animal model. Recently, we developed such a knock-in mouse model for FOP (Acvr1(R206H/+)) that recapitulates the human disease, and provides a valuable new tool for testing and developing effective therapies. The FOP knock-in mouse and other models in Drosophila, zebrafish, chickens and mice provide an arsenal of tools for understanding BMP signaling and addressing outstanding questions of disease mechanisms that are relevant not only to FOP but also to a wide variety of disorders associated with regenerative medicine and tissue metamorphosis.
Topics: Activin Receptors; Animals; Bone Development; Disease Models, Animal; Humans; Metamorphosis, Biological; Mutation; Myositis Ossificans
PubMed: 23115204
DOI: 10.1242/dmm.010280 -
Annals of the New York Academy of... Nov 2011The most important milestone in understanding a genetic disease is the identification of the causative mutation. However, such knowledge is often insufficient to... (Review)
Review
The most important milestone in understanding a genetic disease is the identification of the causative mutation. However, such knowledge is often insufficient to decipher the pathophysiology of the disorder or to effectively treat those affected. Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling, genetic disease of progressive heterotopic endochondral ossification (HEO) enabled by missense mutations that promiscuously and provisionally activate ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor, in all affected individuals. While activating mutations of the ACVR1/ALK2 receptor are necessary, disease activity and progression also depend on altered cell and tissue physiology. Recent findings identify inflammatory and immunological factors, vascular-derived mesenchymal stem cells, and a hypoxic lesional microenvironment that trigger, promote, and enable episodic progression of FOP in the setting of the genetic mutation. Effective therapies for FOP will need to consider these seminal pathophysiologic interactions.
Topics: Activin Receptors, Type I; Animals; Humans; Mutation, Missense; Myositis Ossificans; Stem Cell Transplantation; Stem Cells
PubMed: 22082359
DOI: 10.1111/j.1749-6632.2011.06195.x -
Biomolecules Jan 2024Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (, also known as ) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO.
Topics: Animals; Mice; Ligands; Mutation; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; TOR Serine-Threonine Kinases; Humans; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38397384
DOI: 10.3390/biom14020147 -
Orphanet Journal of Rare Diseases May 2023Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great...
BACKGROUND
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients.
RESULTS
We recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients.
CONCLUSIONS
There were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis.
Topics: Mice; Animals; Myositis Ossificans; Retrospective Studies; Mutation; Ossification, Heterotopic; Bone Morphogenetic Proteins; Activin Receptors, Type I
PubMed: 37165433
DOI: 10.1186/s13023-023-02708-3 -
QJM : Monthly Journal of the... Nov 2021
Topics: COVID-19; COVID-19 Vaccines; Humans; Myositis Ossificans; SARS-CoV-2; Vaccination
PubMed: 34109386
DOI: 10.1093/qjmed/hcab161 -
International Journal of Surgery Case... Jul 2021Myositis ossificans of the hip is a rare entity caused by trauma and neurological conditions which lead to lamellar bone formation around the joint.
INTRODUCTION AND IMPORTANCE
Myositis ossificans of the hip is a rare entity caused by trauma and neurological conditions which lead to lamellar bone formation around the joint.
CASE PRESENTATION
We present a 47 years old patient with myositis ossificans of the left and the piriformis muscle following Guillain Barré syndrome causing sciatic nerve palsy (Piriformis syndrome).
CLINICAL DISCUSSION
Clinical assessment revealed global limitation of the left hip movements and palpable bony mass on the lateral aspect of the left hip. Radiographs and computed tomography showed extensive myositis ossificans of the left hip and non-bridging calcification noted on the asymptomatic right side. During initial medical management and physiotherapy patient developed sciatic nerve palsy due to piriformis syndrome and ankylosis of the hip on the left side. Surgical exploration of the sciatic nerve and debridement of the hip. The left hip was found ankylosed and not salvageable. Uncemented total hip arthroplasty was carried out in the session. The patient recovered completely from sciatic nerve palsy and regained the range of motion of the hip. He is under follow-up for the recurrence of myositis ossificans.
CONCLUSION
Guillain-barré syndrome causing piriformis syndrome is a rare entity. Extensive myositis ossificans causing sciatic nerve palsy is even rarer. An awareness of this entity, early detection, and intervention of this condition may help to preserve the native hip.
PubMed: 34171613
DOI: 10.1016/j.ijscr.2021.106110 -
Genes Jul 2021Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic condition characterized by extraskeletal bone formation. Most of the musculoskeletal characteristics...
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 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.
Topics: Child; Child, Preschool; Female; Humans; Magnetic Resonance Imaging; Male; Myositis Ossificans
PubMed: 34440363
DOI: 10.3390/genes12081187 -
Orphanet Journal of Rare Diseases Dec 2011Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features [FOP plus], or present with major variations in one or both of the two classic defining features of FOP [FOP variants]. Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Although most cases of FOP are sporadic (noninherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern. At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.
Topics: Activin Receptors, Type I; Child; Child, Preschool; Genetic Counseling; Genetic Testing; Humans; Mutation; Myositis Ossificans; Ossification, Heterotopic; Toes
PubMed: 22133093
DOI: 10.1186/1750-1172-6-80 -
Radiology Case Reports Dec 2022Myositis ossificans (MO) is a benign disorder where bone forms within muscles or other soft tissues. This condition usually follows trauma and is rare in pediatric...
Myositis ossificans (MO) is a benign disorder where bone forms within muscles or other soft tissues. This condition usually follows trauma and is rare in pediatric patients. Here we present the case of a 2-year-old male who developed MO of his right elbow without obvious trauma to the area. Imaging of MO in the initial phase is highly unspecific and obtaining tissue samples through a biopsy can render misleading reports. In most cases MO is a self-limited process with complete resolution, however, some cases may present a diagnostic and therapeutic challenge.
PubMed: 36193266
DOI: 10.1016/j.radcr.2022.09.032 -
Cancer Science Mar 2023Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily. BMPs play crucial roles in embryogenesis and bone remodeling.... (Review)
Review
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily. BMPs play crucial roles in embryogenesis and bone remodeling. Recently, BMP signaling has been found to have diverse effects on different types of tumors. In this review, we summarized the effects of BMP signaling on gynecologic cancer. BMP signaling has tumor-promoting effects on ovarian cancer (OC) and endometrial cancer (EC), whereas it has tumor-suppressing effects on uterine cervical cancer (UCC). Interestingly, EC has frequent gain-of-function mutations in ACVR1, encoding one of the type I BMP receptors, which are also observed in fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Little is known about the relationship between BMP signaling and other gynecologic cancers. Tumor-promoting effects of BMP signaling in OC and EC are dependent on the promotion of cancer stemness and epithelial-mesenchymal transition (EMT). In accordance, BMP receptor kinase inhibitors suppress the cell growth and migration of OC and EC. Since both cancer stemness and EMT are associated with chemoresistance, BMP signaling activation might also be an important mechanism by which OC and EC patients acquire chemoresistance. Therefore, BMP inhibitors are promising for OC and EC patients even if they become resistant to standard chemotherapy. In contrast, BMP signaling inhibits UCC growth in vitro. However, the in vivo effects of BMP signaling have not been elucidated in UCC. In conclusion, BMP signaling has a variety of functions, depending on the types of gynecologic cancer. Therefore, targeting BMP signaling should improve the treatment of patients with gynecologic cancer.
Topics: Humans; Female; Bone Morphogenetic Proteins; Transforming Growth Factor beta; Signal Transduction; Myositis Ossificans; Epithelial-Mesenchymal Transition; Neoplasms
PubMed: 36468782
DOI: 10.1111/cas.15682