High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2016-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/9/6/685 |
| _version_ | 1819117081998655488 |
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| author | Serena Cappato Laura Tonachini Francesca Giacopelli Mario Tirone Luis J. V. Galietta Martina Sormani Anna Giovenzana Antonello E. Spinelli Barbara Canciani Silvia Brunelli Roberto Ravazzolo Renata Bocciardi |
| author_facet | Serena Cappato Laura Tonachini Francesca Giacopelli Mario Tirone Luis J. V. Galietta Martina Sormani Anna Giovenzana Antonello E. Spinelli Barbara Canciani Silvia Brunelli Roberto Ravazzolo Renata Bocciardi |
| author_sort | Serena Cappato |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T05:27:19Z |
| format | Article |
| id | doaj.art-bc8881ef03a44f499df1f39179097a51 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-22T05:27:19Z |
| publishDate | 2016-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-bc8881ef03a44f499df1f39179097a512022-12-21T18:37:32ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112016-06-019668569610.1242/dmm.023929023929High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressivaSerena Cappato0Laura Tonachini1Francesca Giacopelli2Mario Tirone3Luis J. V. Galietta4Martina Sormani5Anna Giovenzana6Antonello E. Spinelli7Barbara Canciani8Silvia Brunelli9Roberto Ravazzolo10Renata Bocciardi11 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano 20132, Italy Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy Medical Physics Department and Centre for Experimental Imaging, San Raffaele Scientific Institute, Milano 20132, Italy Dipartimento di Medicina Sperimentale, Università di Genova & IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova 16132, Italy 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.http://dmm.biologists.org/content/9/6/685ACVR1Transcriptional regulationBMP signaling pathwayFOPDipyridamoleHigh-throughput screeningDrug repositioning |
| spellingShingle | Serena Cappato Laura Tonachini Francesca Giacopelli Mario Tirone Luis J. V. Galietta Martina Sormani Anna Giovenzana Antonello E. Spinelli Barbara Canciani Silvia Brunelli Roberto Ravazzolo Renata Bocciardi High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva Disease Models & Mechanisms ACVR1 Transcriptional regulation BMP signaling pathway FOP Dipyridamole High-throughput screening Drug repositioning |
| title | High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva |
| title_full | High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva |
| title_fullStr | High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva |
| title_full_unstemmed | High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva |
| title_short | High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva |
| title_sort | high throughput screening for modulators of acvr1 transcription discovery of potential therapeutics for fibrodysplasia ossificans progressiva |
| topic | ACVR1 Transcriptional regulation BMP signaling pathway FOP Dipyridamole High-throughput screening Drug repositioning |
| url | http://dmm.biologists.org/content/9/6/685 |
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