Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification
Abstract Heterotopic ossification (HO) is the pathological formation of ectopic endochondral bone within soft tissues. HO occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). FOP patients carry a conserved mutation in ACVR...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201910567 |
| _version_ | 1827015096615829504 |
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| author | José Antonio Valer Cristina Sánchez‐de‐Diego Beatriz Gámez Yuji Mishina José Luis Rosa Francesc Ventura |
| author_facet | José Antonio Valer Cristina Sánchez‐de‐Diego Beatriz Gámez Yuji Mishina José Luis Rosa Francesc Ventura |
| author_sort | José Antonio Valer |
| collection | DOAJ |
| description | Abstract Heterotopic ossification (HO) is the pathological formation of ectopic endochondral bone within soft tissues. HO occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). FOP patients carry a conserved mutation in ACVR1 that becomes neomorphic for activin A responses. Here, we demonstrate the efficacy of BYL719, a PI3Kα inhibitor, in preventing HO in mice. We found that PI3Kα inhibitors reduce SMAD, AKT, and mTOR/S6K activities. Inhibition of PI3Kα also impairs skeletogenic responsiveness to BMPs and the acquired response to activin A of the Acvr1R206H allele. Further, the efficacy of PI3Kα inhibitors was evaluated in transgenic mice expressing Acvr1Q207D. Mice treated daily or intermittently with BYL719 did not show ectopic bone or cartilage formation. Furthermore, the intermittent treatment with BYL719 was not associated with any substantial side effects. Therefore, this work provides evidence supporting PI3Kα inhibition as a therapeutic strategy for HO. |
| first_indexed | 2024-03-07T17:32:47Z |
| format | Article |
| id | doaj.art-217f501ce97048ea8484fd1bea57b8fb |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:17:39Z |
| publishDate | 2019-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-217f501ce97048ea8484fd1bea57b8fb2024-10-28T08:58:23ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-08-0111911310.15252/emmm.201910567Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossificationJosé Antonio Valer0Cristina Sánchez‐de‐Diego1Beatriz Gámez2Yuji Mishina3José Luis Rosa4Francesc Ventura5Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELLDepartament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELLDepartament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELLDepartment of Biologic and Materials Sciences, School of Dentistry, University of MichiganDepartament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELLDepartament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELLAbstract Heterotopic ossification (HO) is the pathological formation of ectopic endochondral bone within soft tissues. HO occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). FOP patients carry a conserved mutation in ACVR1 that becomes neomorphic for activin A responses. Here, we demonstrate the efficacy of BYL719, a PI3Kα inhibitor, in preventing HO in mice. We found that PI3Kα inhibitors reduce SMAD, AKT, and mTOR/S6K activities. Inhibition of PI3Kα also impairs skeletogenic responsiveness to BMPs and the acquired response to activin A of the Acvr1R206H allele. Further, the efficacy of PI3Kα inhibitors was evaluated in transgenic mice expressing Acvr1Q207D. Mice treated daily or intermittently with BYL719 did not show ectopic bone or cartilage formation. Furthermore, the intermittent treatment with BYL719 was not associated with any substantial side effects. Therefore, this work provides evidence supporting PI3Kα inhibition as a therapeutic strategy for HO.https://doi.org/10.15252/emmm.201910567bonebone morphogenetic proteinfibrodysplasia ossificans progressivaheterotopic ossificationPI3K |
| spellingShingle | José Antonio Valer Cristina Sánchez‐de‐Diego Beatriz Gámez Yuji Mishina José Luis Rosa Francesc Ventura Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification EMBO Molecular Medicine bone bone morphogenetic protein fibrodysplasia ossificans progressiva heterotopic ossification PI3K |
| title | Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification |
| title_full | Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification |
| title_fullStr | Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification |
| title_full_unstemmed | Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification |
| title_short | Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification |
| title_sort | inhibition of phosphatidylinositol 3 kinase α pi3kα prevents heterotopic ossification |
| topic | bone bone morphogenetic protein fibrodysplasia ossificans progressiva heterotopic ossification PI3K |
| url | https://doi.org/10.15252/emmm.201910567 |
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