Treatment Of Fibrodysplasia Ossificans Progressiva Research Articles

Research trends and hotspots of myositis ossificans: a bibliometric analysis from 1993 to 2022.

Myositis ossificans (MO) is characterized by benign heterotopic ossificans in soft tissues like muscles, which can be classified into nonhereditary MO and fibrodysplasia ossificans progressiva (FOP). Although MO has been studied for decades, no research reviewed and analyzed the features of publications in this field quantitatively and qualitatively. Using bibliometrics tools (bibliometrix R package, VOSviewer, and CiteSpace), we conducted a bibliometric analysis of 1280 articles regarding MO in the Web of Science Core Collection database from 1993 to 2022. The annual number of publications and related research areas in the MO field increased gradually in the past 20 years. The USA contributed the most percentage (42.58%) of articles. The University of Pennsylvania (UPenn) and the Journal Bone published the most articles among all institutions and journals. Kaplan FS and Shore EM from UPenn were the top two scholars who made the largest contributions to this field. Keyword analysis showed that research hotspots changed from traumatic MO and clinical management of MO to the genetic etiology, pathogenesis, and treatment of FOP. This study can provide new insights into the research trends of MO and helps researchers grasp and determine future study directions more easily.

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

Fibrodysplasia Ossificans Progressiva: Literature Review and Case Report

Background. Fibrodysplasia ossificans progressiva (FOP) is a genetic disease of the heterotopic ossification group associated with the mutation in ACVR1/ALK2 gene. FOP is characterized by progressive heterotopic endochondral ossification of connective tissue that occurs in postnatal period. It leads to formation of qualitatively normal bone in extraskeletal areas. Congenital hallux deformity is typical for this disease. The clinical picture is characterized by aggravations that are usually caused by trauma or viral infections. Formation of Heterotopic ossificate formation can be observed during aggravations. There is no etiological treatment for FOP. Systemic glucocorticosteroids, non-steroidal anti-inflammatory drug (NSAIDs), mast cell stabilisers, antileukotriene drugs and bisphosphonates can be used in these patients.Clinical case description. The child was born with congenital hallux deformity typical for FOP. The disease onset was noted at the age of 2 years 8 months with a tumor-like painful mass on the neck. Oncological (lymphoproliferative) disease was suspected but biopsy from the lesion did not confirm its malignant nature. The child was consulted by pediatric rheumatologist who has diagnosed FOP. Etanercept and zoledronic acid were administrated, though etanercept was later discontinued. For now, the child receives zoledronic acid infusions 2 times per year and daily NSAIDs.Conclusion. The difficulties in FOP diagnosing are associated to its sporadic nature and clinical picture similarity to other diseases. Suspected malignancy leads to biopsy that is highly undesirable in FOP patients due to high risk of iatrogenic complications.

The Effects of Palovarotene in Patients with Fibrodysplasia Ossificans Progressiva: A Plain Language Summary

What is this summary about? This is a plain language summary of an article originally published in the Journal of Bone and Mineral Research. People with fibrodysplasia ossificans progressiva (FOP) become physically disabled over time as new bone forms in places where it is not usually found, such as in muscles and ligaments. Until recently, there were no treatments for FOP that had been proven through clinical trials; however, a drug called palovarotene has been tested in clinical trials and may be effective. Here, we describe the MOVE trial, which investigated how effectively palovarotene works, as well as its safety in treating patients with FOP. What were the results? Results from MOVE suggest that palovarotene may reduce extra bone formation outside the normal skeleton. Patients with FOP who took palovarotene formed less new bone than those who did not take palovarotene. The most common side effects involved the skin, and included dryness and irritation. Some children who were still growing when they took palovarotene had a side effect that resulted in the (normal) growth of their skeleton stopping too soon. What do the results of the trial mean? Palovarotene may be a useful treatment option for FOP. Patients, caregivers, and doctors would need to consider the benefits and risks of treatment with palovarotene, particularly with growing children. Clinical Trial Registration: NCT03312634 ( ClinicalTrials.gov )

ODP103 IPN60130 for the Treatment of Fibrodysplasia Ossificans Progressiva: Methodology of the Randomized, Double-Blind, Placebo-Controlled Phase II FALKON Trial

Abstract Objectives Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder caused by activin receptor-like kinase-2/activin A receptor type 1(ALK2/ACVR1) mutation and characterized by heterotopic ossification (HO) inducing progressive restriction of mobility. IPN60130 is a selective ALK2/ACVR1 inhibitor, currently being investigated for the treatment of FOP. 1 Here, we describe methodology of the FALKON trial (NCT05039515) designed to compare efficacy and safety of IPN60130 with placebo in patients with FOP. Methods Patients will be randomized to oral placebo, or low or high dose IPN60130 for 12 months; patients receiving placebo will then transition to IPN60130 for 12 months. Patients will be randomized to receive placebo, or low or high dose IPN60130 orally for 24months. Enrollment criteria include: age of ≥5years, clinical FOP diagnosis with a disease-causing mutation, and either a flare-up, new HO, new joint ankylosis, or increase in Cumulative Analogue Joint Involvement Scale (CAJIS) score in the prior year. Recruitment is ongoing to enroll 90 patients. The primary efficacy outcome will be the annualized change from Baseline (CfB) in HO volume to Month 12, assessed using low-dose whole-body computed tomography (CT). Secondary efficacy outcomes to be compared with placebo at Month 12 include: CfB in volume of new HO lesions, CfB in number of HO lesions, flare-up rate and number of flare-up days, number of body regions with new HO, CfB in pain intensity, and the proportion of patients with any new HO. Additional secondary endpoints include CfB in HO volume in treated patients versus placebo and participants receiving standard of care in a FOP natural history study (NCT02322255) at Month 24. Safety will be assessed via the incidence of adverse events (AEs) and serious AEs over 25 months. Patients aged ≥15 years will be eligible for a sub-study assessing HO using [ 18 F]NaF positron emission tomography-CT. Summary Results from the FALKON trial, expected to complete in August 2025, will enable evaluation of the efficacy and safety of IPN60130 in patients with FOP.

Palovarotene for the treatment of fibrodysplasia ossificans progressiva: methodology of the phase III open-label PIVOINE rollover trial

Palovarotene for the treatment of fibrodysplasia ossificans progressiva: methodology of the phase III open-label PIVOINE rollover trial

IPN60130 for the treatment of fibrodysplasia ossificans progressiva: methodology of the randomized, double-blind, placebo-controlled phase II FALKON trial

IPN60130 for the treatment of fibrodysplasia ossificans progressiva: methodology of the randomized, double-blind, placebo-controlled phase II FALKON trial

Monitoring and Management of Fibrodysplasia Ossificans Progressiva: Current Perspectives.

Fibrodysplasia ossificans progressiva (FOP), sometimes known as myositis ossificans progressiva, is an ultra-rare disease in which bone is formed in muscular tissue, tendons and ligaments. This is known as heterotopic ossification (HO). FOP is caused by a heterozygous mutation in the highly conserved ACVR1/ALK2 gene which affects about 1 in 1.5–2 million individuals. At birth, patients with the predominant R206H mutation only exhibit a bilateral hallux valgus. During childhood, heterotopic bone formation develops in a typical pattern, affecting the axial muscles first before appendicular body parts are involved. HO can start spontaneously but is often elicited by soft tissue trauma or medical procedures. After soft tissue injury, an inflammatory process called a flare-up can start, followed by the formation of HO. HO leads to a limited range of motion, culminating in complete ankylosis of nearly all joints. As a result of HO surrounding the thorax, patients often suffer from thoracic insufficiency syndrome (TIS). TIS is the most common cause of a limited life expectancy for FOP patients, with a median life expectancy of 56 years. Management is focused on preventing soft-tissue injury that can provoke flare-ups. This includes prevention of iatrogenic damage by biopsies, intramuscular injections and surgery. Anti-inflammatory medication is often started when a flare-up occurs but has a poor basis of evidence. Several forms of potential treatment for FOP are being researched in clinical trials. Progression of the disease is monitored using CT and 18F-NaF PET/CT combined with functional assessments. Patients are regularly evaluated for frequently occurring complications such as restrictive lung disease. Here, we review the current management, monitoring and treatment of FOP.

Discovery of a novel 2-aminopyrazine-3-carboxamide as a potent and selective inhibitor of Activin Receptor-Like Kinase-2 (ALK2) for the treatment of fibrodysplasia ossificans progressiva

Inhibition of mutant activin A type-1 receptor ACVR1 (ALK2) signaling by small-molecule drugs is a promising therapeutic approach to treat fibrodysplasia ossificans progressiva (FOP), an ultra-rare disease leading to progressive soft tissue heterotopic ossification with no curative treatment available to date. Here, we describe the synthesis and in vitro characterization of a novel series of 2-aminopyrazine-3-carboxamides that led to the discovery of Compound 23 showing excellent biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and a favorable in vitro ADME profile.

Improving the Diagnosis of Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a distinctive but often-overlooked disorder, owing to its extreme rarity and insidious presentation. However, the signs of classic FOP are evident at birth, and the disease clinically manifests typically within the first decade of life. The characteristic and invariably early sign of FOP is congenital malformation of the great toes (Figure 1). 1 Pignolo R.J. Wang H. Kaplan F.S. Fibrodysplasia ossificans progressiva (FOP): a segmental progeroid syndrome. Front Endocrinol (Lausanne). 2020; 10: 908 Crossref PubMed Scopus (12) Google Scholar , 2 Pignolo R.J. Shore E.M. Kaplan F.S. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011; 6: 80 Crossref PubMed Scopus (159) Google Scholar , 3 National Organization for Rare Disorders [homepage on the Internet]. 2020https://rarediseases.org/rare-diseases/fibrodysplasia-ossificans-progressiva/ Google Scholar In 50% of cases, the thumbs are similarly affected. Other findings at birth may include a broad femoral neck and bony malformation of the cervical spine. 4 Meyers C. Lisiecki J. Miller S. Levin A. Fayad L. Ding C. et al. Heterotopic ossification: a comprehensive review. JBMR Plus. 2019; 3: e10172 Crossref PubMed Scopus (95) Google Scholar , 5 The International Clinical Council on FOP (ICC) and Consultants [homepage on the Internet]. 2019https://d3n8a8pro7vhmx.cloudfront.net/ifopa/pages/212/attachments/original/1559059247/FOP_TREATMENT_GUIDELINES_June_2019.pdf Google Scholar , 6 International Fibrodysplasia Ossificans Progressiva Association (IFOPA) [homepage on the Internet]. 2020www.ifopa.org/what_is_fop Google Scholar Heterotopic ossification, the abnormal growth of bone in extraskeletal tissues, typically is not present at birth, although areas of soft-tissue swelling may be evident in neonates. Infants and children with FOP may present to pediatric orthopedic surgeons with progressive “bunions” or malformed great toes. However, it is rare that the disease is recognized at this stage. In most cases, unfortunately, the diagnosis of FOP is not made until affected persons have consulted several physicians and the associated deformity and disability are undeniable. 7 Kapan F. Xu M. Glaser D.L. Collins F. Connor M. Kitterman J. et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008; 121: e1295-e1300 Crossref PubMed Scopus (113) Google Scholar It is estimated that 3500-4000 people worldwide have FOP, although the disorder has been diagnosed in only about 900 people. 3 National Organization for Rare Disorders [homepage on the Internet]. 2020https://rarediseases.org/rare-diseases/fibrodysplasia-ossificans-progressiva/ Google Scholar Although there are currently no approved treatments for FOP, early recognition and diagnosis is important to prevent unnecessary trauma, such as intramuscular vaccination or surgery, that may induce disease flares.

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.

Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva

Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.

Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti‐Activin A): Results From a First‐in‐Human Phase 1 Study

We describe outcomes from the first‐in‐human study of garetosmab (a fully human monoclonal antibody that inhibits activin A) under development for the treatment of fibrodysplasia ossificans progressiva (FOP). In a double‐blind, placebo‐controlled phase 1 study, 40 healthy women of nonchildbearing potential were randomized to receive a single dose of intravenous garetosmab 0.3, 1, 3, or 10 mg/kg; subcutaneous garetosmab 300 mg; or placebo. Serum concentrations of functional garetosmab (with ≥1 arm free to bind to target), total activin A, and antidrug antibodies were measured predose and up to 113 days post–first dose. Garetosmab demonstrated an acceptable safety profile with no dose‐limiting toxicities. Garetosmab displayed nonlinear pharmacokinetics with target‐mediated elimination. With increasing doses of intravenous garetosmab, mean peak concentration increased in a dose‐proportional manner; mean steady‐state estimates ranged from 41.4 to 47.8 mL/kg. A greater than dose‐proportional increase in mean area under the concentration‐time curve from time zero extrapolated to infinity (range, 72.2‐7520 mg*day/L) was observed, consistent with decreasing mean clearance (range, 4.35‐1.34 mL/day/kg). Following administration of intravenous garetosmab, mean concentrations of total activin A increased in a dose‐dependent manner. At 10 mg/kg, total activin A levels reached a state of little or no change between weeks 4 and 12, suggesting saturation of the target‐mediated pathway. No safety signals were seen in this study to preclude investigation in patients. Following intravenous administration, garetosmab concentrations decreased quickly, then decreased over time (reflecting linear elimination), and finally decreased in a nonlinear phase, reflecting target‐mediated elimination. Results here support further investigation. Garetosmab 10 mg/kg every 4 weeks intravenously is being evaluated in patients with FOP (NCT03188666).

Structural Basis of Activin Receptor-Like Kinase 2 (R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for the Treatment of Fibrodysplasia Ossificans Progressiva Identified by the Integration of Ligand-Based and Structure-Based Drug Design Approaches

Fibrodysplasia ossificans progressiva (FOP) is a rare but severe genetic disorder in which acute inflammation elicits progressive heterotopic ossification in the muscles, tendons, and ligaments. Classic FOP is caused by the R206H mutation in ALK2/ACVR1. While several activin receptor-like kinase 2 (ALK2) inhibitors were found to be efficacious in animal models of FOP, most of the ALK2 (R206H) inhibitors lacked sufficient oral bioavailability for efficacy. Previously, the synthesis of a series of novel bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitors that achieved both substantial potency and an improved ADMET profile was reported. In the present study, the detailed procedure of the in silico approach employed to identify the initial bis-heteroaryl pyrazole-based ALK2 (R206H) inhibitor RK-59638 and the analysis of the ALK2 (R206H) RK-59638 complex structure to guide the synthetic optimization of the chemical series, obtaining RK-71807 showing improved potency and metabolic stability, were described. According to the initial in silico screening, the screening efficiencies and chemical diversity of the hit compounds of both ligand-based and structure-based methods were evaluated. Then, X-ray structures of ALK2 (R206H) and the inhibitors were analyzed to assess the structure–activity relationships of the synthesized compounds. The 3D-RISM analysis indicated the existence of the additional hydrogen bond via water molecules restricting the attachment point in the pyrazole scaffold. The quantum mechanics calculation of the newly determined ALK2 (R206H) RK-71807 complex structure using a fragment molecular orbital method and pair interaction energy decomposition analysis was employed to evaluate the interaction energies between the inhibitor and each of the amino acid residues and decompose them to electrostatic, exchange-repulsion, and charge transfer energies. The pattern of decomposed interaction energies was then compared to that formed by RK-59638 and LDN-193189 to investigate the structural basis of ALK2 (R206H) inhibition.

MON-348 Surgical Management of Bilateral Hip Fracture in a Patient with Fibrodysplasia Ossificans Progressiva Treated with Palovarotene

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder marked by painful, recurrent flare-ups and progressive heterotopic ossification (HO) in soft tissues. The bone formation can be idiopathic or provoked by trauma, illness, or inflammation. There are limited treatment options, with glucocorticoids and non-steroidal anti-inflammatory agents being used for palliative treatment. Palovarotene (PVO), an investigational retinoic acid receptor gamma agonist, offers a potential avenue to prevent HO development. Clinical Case: The patient was a 29 year-old male, diagnosed with FOP at age 9, who enrolled in a study evaluating chronic PVO (5mg/day) for the treatment of FOP. Major joints affected at enrollment were his spine, jaw, shoulders, right hip and ankles. One year after starting PVO, he had a fall that resulted in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received flare-dosing PVO at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Post-surgical imaging 12 weeks after the surgery showed new bridging HO at the site of intramedullary rod insertion and around the distal screw.Nine months after the fracture the patient had a second fall resulting in a right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. PVO was increased similarly to the above flare protocol, but, at the time of fracture occurrence rather than post-surgery. He had no skin or healing complications with either treatment regimen.After each fracture the patient had prolonged recurrent flare-ups at the injury sites, significantly increasing his number of flare-ups per year. After the fractures there was new Brooker class D HO at the left hip, originating at the insertion of the intramedullary rod, and new class B HO at the right greater trochanter, again near the insertion site of the intramedullary rod compared to his pre-surgery baseline. In contrast, there was no new HO at the right distal intramedullary rod whereas HO occurred around the screw placement site at the left distal rod. Conclusion: This case suggests that PVO in the dosing regimen received by this patient can be tolerated in an individual with FOP following major surgery. HO still occurred in this patient, particularly along the rod insertion track, suggesting that the PVO regimen may need to be optimized for surgical cases or that poly-trauma events may not be adequately blocked by the dosing regimen received by this patient. However, PVO did not negatively impact fracture healing or osteointegration, and no major skin healing effects were identified. Further investigation is needed to assess whether PVO can lead to a dose-dependent reduction in HO in the setting of trauma and surgery.

Orphan designation: human monoclonal antibody against activin A, Treatment of fibrodysplasia ossificans progressiva

Orphan designation: human monoclonal antibody against activin A, Treatment of fibrodysplasia ossificans progressiva

Orphan designation: human monoclonal antibody against activin A, Treatment of fibrodysplasia ossificans progressiva

Orphan designation: human monoclonal antibody against activin A, Treatment of fibrodysplasia ossificans progressiva

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva-Derived Endothelial Cells.

ABSTRACTFibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone‐inducing agents. To date, there is no cure for FOP. The further development of FOP patient‐derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood‐derived endothelial colony‐forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial‐to‐mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator

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.

Fibrodysplasia ossificans progressiva: lessons learned from a rare disease.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and severely disabling autosomal dominant disease that is yet to be clearly understood. The purpose of this review is to present recent literature on pathophysiology, clinical features, diagnosis and treatment of FOP. FOP is characterized by congenital great toe deformity and progressive heterotopic ossifications in connective tissue. Heterotopic ossifications occur after painful flare-ups that can arise spontaneously or can be triggered by minor trauma. Each flare-up ultimately causes restriction of related-joint, and along with the others eventually leads to immobility. Death is usually caused by pulmonary complications because of chest wall involvement. The causative gene of FOP is activin A receptor type 1 (ACVR1), a bone morphogenetic protein-signalling component, which normally acts to inhibit osteoblastogenesis. The treatment of FOP is still preventive and supportive. Although there are still gaps in the underlying mechanism of FOP, effective treatment options, such as potential pharmacologic targets and cell-based therapies are promising for the future. Some of these were tested without a clinical trial setting, and are currently in the process of evidence-based research.