PI3Kα inhibition blocks osteochondroprogenitor specification and the hyper-inflammatory response to prevent heterotopic ossification
eLife, vol. 12
Abstract
Heterotopic ossification (HO) occurs following mechanical trauma and burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidylinositol 3-kinase alpha (PI3Kα) may be a useful therapy for patients undergoing HO. In this study, using the already marketed BYL719/Alpelisib/Piqray drug, we have further confirmed these results, detailed the underlying mechanisms of action, and optimized the timing of the administration of BYL719. We found that BYL719 effectively prevents HO even when administered up to 3–7 days after injury. We demonstrate in cell cultures and in a mouse model of HO that the major actions of BYL719 are on-target effects through the inhibition of PI3Kα, without directly affecting ACVR1 or FOP-inducing ACVR1 R206H kinase activities. In vivo, we found that a lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification but also reduces the inflammatory response. BYL719 inhibits the migration, proliferation, and expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
Authors 8
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Institut d'Investigació Biomédica de Bellvitge · Universitat de Barcelona
Affiliation as printed
Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, C/ Feixa Llarga s/n 08907 Hospitalet de Llobregat
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Institut d'Investigació Biomédica de Bellvitge · Universitat de Barcelona
Affiliation as printed
Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, C/ Feixa Llarga s/n 08907 Hospitalet de Llobregat
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands
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Institut d'Investigació Biomédica de Bellvitge · Universitat de Barcelona
Affiliation as printed
Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, C/ Feixa Llarga s/n 08907 Hospitalet de Llobregat
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands
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Institut d'Investigació Biomédica de Bellvitge · Universitat de Barcelona
Affiliation as printed
Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, C/ Feixa Llarga s/n 08907 Hospitalet de Llobregat
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Consejo Superior de Investigaciones Científicas · Leiden University Medical Center · Nanomaterials and Nanotechnology Research Center · Instituto de Investigación Sanitaria del Principado de Asturias
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center
Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA)
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands; Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), 33011 Oviedo, Asturias, Spain
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Institut d'Investigació Biomédica de Bellvitge · Universitat de Barcelona
Affiliation as printed
Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, C/ Feixa Llarga s/n 08907 Hospitalet de Llobregat
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