ArticleScience translational medicine2015
ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.
Article in Science translational medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 292 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
292 citing papers in PubMed, 1 synthesis or guideline pooled it, 441 citations in OpenAlex.
- When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature.Frontiers in endocrinology · 2020Pooled it
- Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial.JBMR plus · 2026Trial
- GDF8 and activin A are the key negative regulators of muscle mass in postmenopausal females: a randomized phase I trial.Nature communications · 2025Trial
- Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults.European journal of drug metabolism and pharmacokinetics · 2025Trial
- Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2024Trial
- Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.Nature medicine · 2023Trial
- Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study.Journal of clinical pharmacology · 2020Trial
- BCX9250 is a potent small-molecule inhibitor of Activin A Receptor Type 1 (ACVR1/ALK2) for fibrodysplasia ossificans progressiva.JBMR plus · 2026Article
- Pathogenic transcriptional reprogramming of fibro-adipogenic progenitors in mice with FOP and its mitigation by inhibition of ACVR1 and activin A.bioRxiv : the preprint server for biology · 2026Article
- Macrophage-driven pathological ossification of the posterior longitudinal ligament: mechanistic insights and therapeutic opportunities.Bone research · 2026Review
- A closed-loop cell therapy engineered to autonomously secrete activin A inhibitor protects from fibrodysplasia ossificans progressiva.iScience · 2026Article
- Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage-fibroadipogenic progenitors crosstalk.Cellular and molecular life sciences : CMLS · 2026Article
- Single-base 2'OMe-modified LNA and MOE gapmers selectively silenceMolecular therapy. Nucleic acids · 2026Article
- Precision RNAi for Fibrodysplasia Ossificans Progressiva: a combinatorial, unimolecular, allele selective approach.Research square · 2026Article
- Article
- Heterotopic Ossification: Molecular Drivers, Subtype-Specific Mechanisms, and Translational Therapeutic Advances.Biomolecules · 2026Review
- Content Validation of the Flares Diary: A Qualitative Analysis of the Flares Experience Within the Fibrodysplasia Ossificans Progressiva (FOP) Population.Advances in therapy · 2026Article
- Primary Cilia Are Required for Efficient BMP Signaling in Traumatic Heterotopic Ossification.Biomedicines · 2026Article
- Activin A secretion by muscle-repairing macrophages induces heterotopic ossification in mice.The Journal of clinical investigation · 2026Article
- A bio-inspired computational pipeline for antibody screening and repurposing.Briefings in bioinformatics · 2026Article
232 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors at 1 institution in 1 country.
Funding
Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1(R206H)) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1(R206H) mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1(R206H) causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.