Inhibition of phosphatidylinositol 3‐kinase α ( PI 3Kα) prevents heterotopic ossification

Abstract

Heterotopic ossification (HO) is the pathological formation ofectopic endochondral bone within soft tissues. HO occurs followingmechanical trauma, burns, or congenitally in patients sufferingfrom fibrodysplasia ossificans progressiva (FOP). FOP patients carrya conserved mutation inACVR1that becomes neomorphic foractivin A responses. Here, we demonstrate the efficacy of BYL719,aPI3Kainhibitor, in preventing HO in mice. We found that PI3Kainhibitors reduce SMAD, AKT, and mTOR/S6K activities. Inhibitionof PI3Kaalso impairs skeletogenic responsiveness to BMPs and theacquired response to activin A of theAcvr1R206Hallele. Further, theefficacy of PI3Kainhibitors was evaluated in transgenic miceexpressingAcvr1Q207D. Mice treated daily or intermittently withBYL719did not show ectopic bone or cartilage formation. Further-more, the intermittent treatment with BYL719was not associatedwith any substantial side effects. Therefore, this work providesevidence supporting PI3Kainhibition as a therapeutic strategy forHO.