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Inhibition of phosphatidylinositol 3-kinase ? (PI3K?) prevents heterotopic ossification.

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

SUBMITTER: Valer JA

PROVIDER: S-EPMC6728602 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Valer José Antonio JA Sánchez-de-Diego Cristina C Gámez Beatriz B Mishina Yuji Y Rosa José Luis JL Ventura Francesc F

EMBO molecular medicine 20190802 9

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 activi ...[more]

PMID: 31373426

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Project description:BackgroundTraumatic heterotopic ossification (THO) is a devastating sequela following traumatic injuries and orthopedic surgeries. To date, the exact molecular mechanism of THO formation is still unclear, which hinders the development of effective treatments. The process of THO formation is believed to recapitulate a series of spatiotemporal cellular and signaling events that occur during skeletal development. The Notch signaling pathway is a critical genetic regulator in embryological bone development and fracture healing. However, few data are available concerning whether Notch signaling regulates THO development and maturation.MethodsWe firstly detected the expressions of Notch target genes in both mouse and human THO samples with quantitative RT-PCR and immunohistochemistry (IHC). Then, tissue-resident mesenchymal progenitor cells (TMPCs) were isolated, and the abilities of the proliferation and osteogenic and chondrogenic differentiation of TMPCs were examined under the intervention of the gamma-secretase inhibitor-DAPT at different time points. Finally, DAPT was also administrated in THO mice by burn and Achilles tenotomy injury, and ectopic cartilage and bone formation were monitored by histology and micro-CT.ResultsSeveral Notch target genes were upregulated in both mouse and human THO tissues. Sustained Notch signaling inhibition by DAPT reduced proliferation, osteogenic and chondrogenic differentiation of TMPCs in a time-dependent manner. Moreover, DAPT administration within 3 weeks could inhibit ectopic cartilage and bone formation in a mouse THO model without affecting the total body bone mass.ConclusionsThe Notch signaling serves as an important therapeutic target during THO formation. And sustained gamma-secretase inhibition by DAPT has great potential in repressing chondrogenic and osteogenic differentiation of TMPCs, as well as inhibited ectopic cartilage and bone formation in vivo.The translational potential of this articleSustained Notch inhibition via systemic DAPT (or other similar gamma-secretase inhibitors) administration has promising clinical utility for inhibiting THO formation, providing new insight into THO prophylaxis and treatment.

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Inhibition of phosphatidylinositol 3-kinase ? (PI3K?) prevents heterotopic ossification.

Publications

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

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