High-throughput screening for modulators of ACVR1 transcription: Discovery of potential therapeutics for fibrodysplasia ossificans progressiva

Serena Cappato, Laura Tonachini, Francesca Giacopelli, Mario Tirone, Luis Juan V Galietta, Martina Sormani, Anna Giovenzana, Antonello Spinelli, Barbara Canciani, Silvia Brunelli, Roberto Ravazzolo, Renata Bocciardi

Research output: Contribution to journalArticlepeer-review


The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet antiaggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad-dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo. Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification.

Original languageEnglish
Pages (from-to)685-696
Number of pages12
JournalDMM Disease Models and Mechanisms
Issue number6
Publication statusPublished - Jun 1 2016


  • ACVR1
  • BMP signaling pathway
  • Dipyridamole
  • Drug repositioning
  • FOP
  • High-throughput screening
  • Transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)


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