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Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

ABSTRACT: Heterotopic ossification (HO) is a non-physiological process of bone formation in which progenitor cells in soft tissues differentiate into chondrogenic cells. In the case of fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated-ACVR1/mTORC1 cascade induces HO in progenitors, one of which is the fibro/adipogenic progenitors (FAPs) in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenchymal stem cells derived from induced pluripotent stem cells (iPSCs) of FOP patients. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, in conjunction with an upregulation of mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, and IACS-010759, an inhibitor of OXPHOS, inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of FAP genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221128 | GEO | 2024/02/16

REPOSITORIES: GEO

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Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

Project description:Heterotopic ossification (HO) is a non-physiological process of bone formation in which progenitor cells in soft tissues differentiate into chondrogenic cells. In the case of fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated-ACVR1/mTORC1 cascade induces HO in progenitors, one of which is the fibro/adipogenic progenitors (FAPs) in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenchymal stem cells derived from induced pluripotent stem cells (iPSCs) of FOP patients. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, in conjunction with an upregulation of mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, and IACS-010759, an inhibitor of OXPHOS, inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of FAP genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.

2024-02-16 | GSE220725 | GEO

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Project description:Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients' tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.

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Palovarotene action against heterotopic ossification includes the inhibition of local participating activin-A expressing cell populations

Project description:Heterotopic ossification (HO) consists of extraskeletal bone formation. One form of HO is acquired and instigated by traumas or surgery, and another form is genetic and characterizes Fibrodysplasia Ossificans Progressiva (FOP). We and others showed that activin A promotes both acquired and genetic HO and found that the retinoid agonist Palovarotene inhibits both HO forms in mice. We asked whether Palovarotene's action against HO may include an interference with endogenous activin A expression and/or function. Using a mouse model of acquired HO, we found that activin A and its encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in untreated mice. Single cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in untreated HO, in addition to its expected expression in inflammatory cells and macrophages. Palovarotene administration caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq datasets indicated that the drug had reduced interactions and crosstalk amongst cell populations. Our data reveal that Palovarotene markedly reduces the number of local Inhba-expressing HO-forming populations.

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PI3Kα inhibition blocks osteochondroprogenitor specification and the hyper-inflammatory response to prevent heterotopic ossification

Project description:Heterotopic ossification (HO) occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidyl-inositol 3-kinase alpha (PI3Kα), including the already marketed BYL719/Alpelisib/Piqray, may become a useful therapy for patients undergoing HO. In this study, we have confirmed these results and optimized the timing of administration of BYL719. We found that BYL719 effectively prevents HO when administered even up to three to seven 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 inhibition of PI3Kα, without directly affecting ACVR1/ALK2 kinase activity. In vivo, we found that 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, the proliferation, and the expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. As part of this study, we have conducted bulk RNA sequencing using human mesenchymal stem cells (hMSCs) expressing ACVR1/ALK2-R206H to assess molecular effectors driving the therapeutic potential of BYL719 in FOP. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.

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Palovarotene action against heterotopic ossification includes the inhibition of local participating activin A-expressing cell populations

Project description:Heterotopic ossification (HO) consists of endochondral bone forming at extraskeletal anatomical sites. One form of HO is acquired and instigated by traumas or invasive surgery, and another form is genetic and severe and characterizes patients with Fibrodysplasia Ossificans Progressiva (FOP). Previously, we showed that the synthetic retinoid agonist Palovarotene inhibits both acquired and genetic HO, and we and others subsequently showed that systemic administration of a neutralizing activin A antibody reduces both HO forms as well. Here, we asked whether Palovarotene’s action includes an interference with endogenous activin A expression and/or participation in HO. Using a standard mouse model of acquired HO, we found that activin A protein and encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in control untreated mice. Single cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in control HO, in addition to its expected expression in inflammatory cells and macrophages particularly. Palovarotene administration (4 mg/kg/day/gavage) caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq datasets indicated that the drug had reduced interactions and crosstalk amongst local cell populations. To determine if Palovarotene inhibited Inhba expression directly, we tested it in primary cultures of growth plate chondrocytes. Drug treatment inhibited cartilage phenotypic expression but not Inhba expression. Our data reveal that Palovarotene intersects with activin A during its anti-HO action and markedly reduces the number of local participating Inhba-expressing cell populations. The data broaden the spectrum of HO culprits against which Palovarotene acts, accounting for its therapeutic effectiveness.

2024-06-01 | GSE227253 | GEO

Activin A promotes the development of acquired heterotopic ossification and is an effective target for disease attenuation in mice

Project description:Heterotopic ossification (HO) is a common, potentially debilitating, acquired pathology that is instigated by tissue damage or other insults and involves inflammation followed by chondrogenesis, osteogenesis and extraskeletal bone accumulation. Current standard of care are not very effective and have side effects, making the search for new treatments urgent. Activin A is a member of the transforming growth factor-b (TGF-b) superfamily, is produced by activated macrophages and other inflammatory cells and signals through activation of canonical SMAD2 and SMAD3 (SMAD2/3) intracellular effectors. Because HO starts with inflammation and because pSMAD2/3 activation is chondrogenic, here we tested whether activin A stimulates HO development. Using standard mouse models of acquired intramuscular and subdermal HO, we found that systemic administration of a neutralizing activin A antibody markedly reduced HO development and bone accumulation. Single-cell RNAseq and developmental trajectories showed that the antibody treatment had sharply reduced the number of Sox9+ skeletal progenitors, many of which also expressed the gene encoding activin A (Inhba), that were recruited to the HO site. In line with the latter finding, gain-of-function assays showed that treatment of progenitors with recombinant activin A enhanced their chondrogenic differentiation and did so through SMAD2/3 signaling, and inclusion of activin A to HO-inducing in vivo implants enhanced HO development. Together, our data reveal that activin A is a critical upstream signaling stimulator of HO in mice and could represent an effective therapeutic target against acquired forms of this pathology in patients.

2021-01-01 | GSE157679 | GEO

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