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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

Recapitulation of the pro-inflammatory signature of monocytes with ACVR1 mutation using FOP patient-derived iPSCs

Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A/ALK2 gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated. Here we investigated this issue using immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation-rescued iPSCs (resFOP-ML). Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an up-regulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile consistent with FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with the up-regulation of inflammation-associated genes, some of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signals demonstrated that Activin-A-induced genes, such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML, including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the in vitro experiments. These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes in FOP and its combination with resFOP-ML is useful for investigating the molecular events at the initial inflammation stage of HO in FOP.

2022-05-12 | GSE183525 | GEO

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

Project description:NOTCH1-mutated T-ALL is a feasible target for OxPhos inhibitors owing to its significantly upregulated mitochondrial machinery. Mitochondrial OxPhos can be effectively targeted by the novel inhibitor of mitochondrial complex I IACS-010759, which demonstrated preclinical activity in NOTCH1-mutated T-ALL

2022-04-05 | GSE167305 | GEO

Combinatorial targeting of MYC/BCL2 double-hit lymphoma with mitochondrial complex I and BCL2 inhibitors

Project description:Activation of the MYC oncogene is common in B-cell lymphomas, and frequently associated with compensatory events that dampen Myc-induced apoptosis, such as over-expression of anti-apoptotic Bcl2-family proteins. For example, concurrent translocations of MYC and BCL2 in a subset of Diffuse large B-cell lymphoma (DLBCL) lead to the high-grade “double-hit” lymphoma subtype (DHL), characterized by dismal prognosis in the face of current front-line regimens, thus calling for the pursuit of tailored therapeutic strategies. Here, we show that Myc and Bcl2 modulate the sensitivity of B-cells to IACS-010759, a selective inhibitor of mitochondrial respiratory complex I. Myc activation in non-transformed lymphoid precursors suppressed endogenous Bcl2 and sensitized the cells to IACS-010759-induced apoptosis. Treatment with the Bcl2 inhibitor venetoclax also sensitized to IACS-010759, while overexpression of Bcl-2 was protective. IACS-010759 engaged an ATF4-driven Integrated Stress Response (ISR) with dual anti- and pro-apoptotic effects, the latter mediated by the CHOP transcription factor, which contributed to selective killing of Myc-overexpressing cells. In line with the above data, IACS-010759 and venetoclax synergized in killing human DHL cells, and showed strong combinatorial effects in a pre-clinical setting. In a Bcl2-negative Burkitt’s lymphoma cell line, instead, IACS-010759 synergized with the Mcl-1 inhibitor S63845. Altogether, our data point to the combination of IACS-010759 with distinct Bcl2-family inhibitors for therapeutic reactivation of the intrinsic apoptotic pathway in Myc-associated B-cell lymphomas

2022-03-01 | GSE149073 | GEO

Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers

Project description:<p>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.Insert information here such as publication abstract</p>

2023-06-27 | MTBLS3342 | MetaboLights

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.

2023-07-01 | GSE233843 | GEO

Control and FOP Human iPSC derived myogenic cell single cell RNA sequencing

Project description:We compared the transcriptome of sorted muscle stem/progenitor cells differentiated from control and FOP (ACVR1 R206H (c.617>A)) human induced pluripotent stem cells.

2021-12-29 | GSE151918 | 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

Wisp inhibits chondrogenic differentiation in heterotopic ossification

Project description:Heterotopic ossification (HO) is the formation of extra-skeletal bone in muscle and soft tissues. Better characterization of the signaling pathways predisposing to HO is critical to identifying therapies directed against this common and potentially debilitating condition. WISP-1 (WNT1-inducible-signaling pathway protein 1) is a CCN family member and is expressed in skeletal cells during bone development or repair. Here, we sought to comprehensively explore the significance of WISP-1 across mouse and human HO. Among CCN family members, local Wisp1 expression was most highly upregulated within experimental trauma-associated HO by RNA sequencing, and increased Wisp1 corresponded to gene markers of osteochondral differentiation. WISP1 immunolocalization demonstrated conserved expression in osteochondral cells across mouse and human HO, including an FOP-like model, post-traumatic model, and human examples of non-genetic HO. Transgenic Wisp1 global knockout demonstrated an increase in cartilage and bone in a trauma-induced HO model. Microarray and in vitro culture of Wisp1 null cells suggested that WISP1 functions as a negative regulator of chondrogenic differentiation, and that Wisp1 deletion results in unrestrained endochondral HO formation. siRNA mediated WISP1 knockdown in human progenitor cells confirmed this finding. Overall, these findings suggest that endogenous WISP1 has pathophysiologic relevance in trauma-induced HO and functions as a negative regulator of ectopic chondrogenesis.

2020-06-08 | GSE127956 | GEO

Global gene expression profiling of FOP- or resFOP-iMSCs after chondrogenic differentiation

Project description:Comparison of gene expressions among FOP- or resFOP-iMSCs after chondrogenic differentiation with or without Activin-A. Comparison of gene expressions among FOP- or resFOP-iMSCs after chondrogenic differentiation with or without Activin-A.

2015-12-09 | E-GEOD-69459 | biostudies-arrayexpress

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