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Transcriptomic differences underlying the Activin-A induced large osteoclast formation in both healthy control and Fibrodysplasia Ossificans Progressiva osteoclasts

ABSTRACT: Activin-A has been identified as the driver for heterotopic ossification in FOP. It's effect on osteoclast formation is not extensively studied in control or FOP samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228522 | GEO | 2023/04/07

REPOSITORIES: GEO

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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

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

The role of Activin A in the development of heterotopic ossification

Project description:The role of Activin A in the development of heterotopic ossification

| PRJNA944238 | ENA

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

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

Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

2024-02-16 | GSE221128 | GEO

Transcriptomic differences underlying the Activin-A induced large osteoclast formation in both healthy control and Fibrodysplasia Ossificans Progressiva osteoclasts

Project description:Transcriptomic differences underlying the Activin-A induced large osteoclast formation in both healthy control and Fibrodysplasia Ossificans Progressiva osteoclasts

| PRJNA950087 | ENA

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

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

| PRJNA944240 | ENA

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

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

| PRJNA978081 | ENA

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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