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Title: Inhibition of phosphatidylinositol 3-kinase α (PI3Kα) prevents heterotopic ossification
Author: Valer, José Antonio
Sánchez de Diego, Cristina
Gamez Molina, Beatriz
Mishina, Yuji
Rosa López, José Luis
Ventura Pujol, Francesc
Keywords: Malalties dels ossos
Proteïnes quinases
Bone diseases
Protein kinases
Issue Date: 2-Aug-2019
Publisher: EMBO Press
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.
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It is part of: EMBO Molecular Medicine, 2019, vol. 11, num. 9, p. e10567
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ISSN: 1757-4676
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Fisiològiques)

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