RRC ID 77022
Author Cappato S, Tonachini L, Giacopelli F, Tirone M, Galietta LJ, Sormani M, Giovenzana A, Spinelli AE, Canciani B, Brunelli S, Ravazzolo R, Bocciardi R.
Title High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva.
Journal Dis Model Mech
Abstract 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 anti-aggregant. 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.
Volume 9(6)
Pages 685-96
Published 2016-6-1
DOI 10.1242/dmm.023929
PII dmm.023929
PMID 27125279
PMC PMC4920148
MeSH Activin Receptors, Type I / genetics* Animals Biomarkers / metabolism Bone Morphogenetic Proteins / metabolism Calcium / metabolism Cell Differentiation / drug effects Cell Line Chondrogenesis / drug effects Dipyridamole / pharmacology Dipyridamole / therapeutic use Disease Models, Animal High-Throughput Screening Assays / methods* Mice Myositis Ossificans / drug therapy* Myositis Ossificans / metabolism Myositis Ossificans / pathology Ossification, Heterotopic / diagnostic imaging Ossification, Heterotopic / pathology Osteoblasts / cytology Osteoblasts / drug effects Osteoblasts / metabolism Osteogenesis / drug effects Reproducibility of Results Signal Transduction / drug effects Smad Proteins / metabolism Transcription, Genetic* / drug effects
IF 4.651
Human and Animal Cells ATDC5(RCB0565)