Inhibition of phosphatidylinositol 3-kinase α (PI3Kα) prevents heterotopic ossification

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 PI3K alpha inhibitor, in preventing HO in mice. We found that PI3K alpha inhibitors reduce SMAD, AKT, and mTOR/S6K activities. Inhibition of PI3K alpha also impairs skeletogenic responsiveness to BMPs and the acquired response to activin A of the Acvr1(R206H) allele. Further, the efficacy of PI3K alpha inhibitors was evaluated in transgenic mice expressing Acvr1(Q207D). 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 PI3K alpha inhibition as a therapeutic strategy for HO.