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 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 Acvr1 R206H allele. Further, the efficacy of PI3Kα 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 PI3Kα inhibition as a therapeutic strategy for HO. Synopsis Heterotopic ossification is a pathological process of endochondral bone formation at extraskeletal sites. Clinical therapy is now limited to symptomatic treatments. This study proposes PI3Kα inhibitors as a potential therapeutic strategy for heterotopic ossification. PI3Kα inhibitors reduce the specification of mesenchymal progenitors into skeletal lineages. PI3Kα inhibition with BYL719 was effective at suppressing heterotopic ossification in vivo . Intermittent treatment with BYL719 was not associated with substantial side effects. Graphical Abstract Heterotopic ossification is a pathological process of endochondral bone formation at extraskeletal sites. Clinical therapy is now limited to symptomatic treatments. This study proposes PI3Kα inhibitors as a potential therapeutic strategy for heterotopic ossification.