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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.

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.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP ( Acvr1 tnR206H ). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1 R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP. Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.

ObjectiveFibrodysplasia ossificans progressiva is a rare genetic disorder characterized by congenital skeletal deformities and soft tissue masses that progress to heterotopic ossification. Deformities of the great toes are distinctive, and heterotopic ossification in the soft tissues follows an expected anatomic and temporal pattern. In addition to heterotopic ossification, osteochondromata, middle ear ossification, demyelination, lymphedema, and venous thrombosis are characteristic. Awareness of this constellation of findings is important to early diagnosis and surveillance.ConclusionsRecognition of the imaging manifestations of fibrodysplasia ossificans progressiva is imperative to early diagnosis in order to appropriately direct patient care and preclude unnecessary biopsies or surgical procedures.

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 gene encoding the bone morphogenetic protein (BMP) type I receptor, ACVR1 (ALK2), the most prevalent of which results in an arginine to histidine substitution at position 206 (ACVR1[R206H]). The fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in fibro-adipogenic progenitors (FAPs), which drives HO. We developed a monoclonal blocking antibody (JAB0505) against the extracellular domain of ACVR1 and tested its effect on HO in 2 independent FOP mouse models. Although JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines, JAB0505 treatment profoundly exacerbated injury-induced HO. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. This was accompanied by dysregulated FAP population growth and an abnormally sustained immunological reaction following muscle injury. JAB0505 drove injury-induced HO in the absence of activin A, indicating that JAB0505 has receptor agonist activity. These data raise serious safety and efficacy concerns for the use of bivalent anti-ACVR1 antibodies to treat patients with FOP.

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. Bone morphogenetic protein (BMP) secretion from cancer cells and carcinoma‐associated mesenchymal stem cells (CA‐MSCs) is triggered by chemotherapy and cancer‐secreted Hedgehog, respectively. Once secreted, BMP ligands enhance cancer proliferation and stemness via c‐KIT induction and also trigger EMT through SNAIL/SLUG induction, leading to the enhancement of migration and invasion. These effects are partially attributed to FN14 induction.

Background Myositis ossificans describes a heterotopic bone formation within a muscle. Thereby myositis ossificans is classified in two different groups: myositis ossificans progressiva (MOP) which describes a genetic autosomal dominant rare disease and myositis ossificans traumatica (MOT). The exact pathogenesis of MOT is unclear. The aim of this article was to analyse and interpret the existing literature reporting MOT of masticatory muscles and compare the results with our own clinical experience with MOT. Risk-factors, etiology, clinical features, diagnostic imaging, as well as different treatment options were evaluated and recommendations for the prevention, diagnosis, and therapy of MOT of the masticatory muscles were given. Methods Following the PRISMA-Guidelines, a systematic search within the PubMed/Medline database with a view to record literature of MOT of the masticatory muscles was performed. Furthermore, the database of our own clinic was screened for cases of MOT. Results In total, 63 cases of MOT of the masticatory muscles which were reported in English-based literature were included in this study. Overall, 25 female and 37 male patients could be analysed whereas one patient’s gender was unknown. Complication of wisdom-tooth infection ( n  = 3) as well as the results of dental procedures like dental extraction ( n  = 7), mandibular nerve block ( n  = 4), periodontitis therapy ( n  = 1) were reported as MOT cases. From the 15 reported cases that appeared after dental treatment like extraction or local anesthesia the medial pterygoid ( n  = 10) was the most affected muscle. Hereof, females were more affected ( n  = 9) than males ( n  = 6). The most reported clinical symptom of MOT was trismus ( n  = 54), followed by swelling ( n  = 17) and pain ( n  = 13). One clinical case provided by the authors was detected. Conclusions Dental procedures, such as local anesthesia or extractions, may cause MOT of the masticatory musculature. Demographical analyses demonstrate that females have a higher risk of developing MOT with respect to dental treatment. The most important treatment option is surgical excision. Subsequent physical therapy can have beneficial effects. Nevertheless, a benefit of interpositional materials and drugs as therapy of MOT of the masticatory muscles has not yet been proven. Myositis ossificans progressiva has to be excluded.

Palovarotene (Sohonos™) is an orally bioavailable selective retinoic acid receptor (RAR)γ agonist being developed by Ipsen for the reduction of heterotopic ossification (HO) formation in patients with fibrodysplasia ossificans progressiva (FOP). By binding to RARγ, palovarotene inhibits bone morphogenetic protein and SMAD 1/5/8 signalling: interfering with these pathways prevents chondrogenesis and ultimately HO by permitting normal muscle tissue repair or regeneration to occur. Palovarotene received its first approval on 21 January 2022 to reduce the formation of HO in adults and children aged 8 years and above for females and 10 years and above for males with FOP in Canada. This article summarizes the milestones in the development of palovarotene leading to this first approval.

Heterotopic ossification is the most disabling feature of fibrodysplasia ossificans progressiva, an ultra-rare genetic disorder for which there is currently no prevention or treatment. Most patients with this disease harbor a heterozygous activating mutation (c.617 G > A;p.R206H) in ACVR1. Here, we identify recombinant AAV9 as the most effective serotype for transduction of the major cells-of-origin of heterotopic ossification. We use AAV9 delivery for gene replacement by expression of codon-optimized human ACVR1, ACVR1R206H allele-specific silencing by AAV-compatible artificial miRNA and a combination of gene replacement and silencing. In mouse skeletal cells harboring a conditional knock-in allele of human mutant ACVR1 and in patient-derived induced pluripotent stem cells, AAV gene therapy ablated aberrant Activin A signaling and chondrogenic and osteogenic differentiation. In Acvr1(R206H) knock-in mice treated locally in early adulthood or systemically at birth, trauma-induced endochondral bone formation was markedly reduced, while inflammation and fibroproliferative responses remained largely intact in the injured muscle. Remarkably, spontaneous heterotopic ossification also substantially decreased in in Acvr1(R206H) knock-in mice treated systemically at birth or in early adulthood. Collectively, we develop promising gene therapeutics that can prevent disabling heterotopic ossification in mice, supporting clinical translation to patients with fibrodysplasia ossificans progressiva. Fibrodysplasia ossificans progressiva is an ultra-rare genetic disorder with progressive heterotopic ossification. Yang et al develop different gene therapy approaches and show their efficacy in mouse models and in human induced pluripotent stem cells.

Background Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant ultra-rare disease characterized by progressive episodic multi-focal heterotopic ossification of skeletal muscle, ligaments, tendons, and fascia. Comprehensive characterization and understanding of the natural disease history of FOP, including mortality, comorbidities, and medication use, is currently limited. Objective This systematic review, which we believe is the first of its kind, aims to synthesize current knowledge on the morbidity, mortality, and medication use associated with FOP. Methods A systematic literature review (SLR) was conducted utilizing various databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, the Trip database, and National Institute for Health and Care Excellence documents. The search was limited to studies involving humans, but was not restricted based on language. The studies used reported at least one of the following outcomes: mortality, comorbidity, and medication use; any clinical trials that were solely designed to evaluate a symptomatic treatment for FOP, such as flare-ups and pain, were excluded. Two independent reviewers reviewed and selected the included studies of the review, and extraction was done by one reviewer with cross-check performed by the other person. The Joanna Briggs Institute Critical Appraisal Checklist, specifically designed for studies reporting prevalence data, was used to assess the quality of studies. The SLR was registered on Prospero (CRD42022366914). Results In total, 32 publications were selected for review. These studies included a wide range of participants age (0.1–78 years), study duration (1 day–33 years), and sample size (3–299 patients). Ten studies reported information on mortality, 26 studies reported on comorbidities, and 12 reported information on medication use. The three organ systems most affected by the conditions studied were, in order of severity, the cardiovascular (40–70%), skeletal (50–65%), and respiratory (20–42%). Conclusions Although FOP is an ultra-rare disease, the available literature demonstrates that it is associated with excess morbidity and mortality. Our review synthesized all available published estimates of epidemiologic landscape of FOP and demonstrates the need for future work to better understand this rare disease.