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The role of Activin A in the development of heterotopic ossification

ABSTRACT: The role of Activin A in the development of heterotopic ossification

PROVIDER: PRJNA944238 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR12611000.fastq.gz	Fastqsanger.gz
	SRR12611001.fastq.gz	Fastqsanger.gz
	SRR12611002.fastq.gz	Fastqsanger.gz
	SRR12611003.fastq.gz	Fastqsanger.gz

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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

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

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

Interorgan communication in the neurogenic heterotopic ossification: focusing on the role of brain-derived extracellular vesicles

Project description:Brain-derived extracellular vesicles participate in inter-organ communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome related proteins encapsulated in brain-derived extracellular vesicles are capable of crossing the blood-brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification that combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon identified the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlighted the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offered a potential strategy for the prevention of neurogenic heterotopic ossification after traumatic brain injury.

2023-11-02 | PXD046626 |

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

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

| PRJNA662374 | ENA

Wisp inhibits chondrogenic differentiation in heterotopic ossification

Project description:Wisp inhibits chondrogenic differentiation in heterotopic ossification

| PRJNA525862 | ENA

Rat heterotopic ossification model proteome

Project description:The mechanism of heterotopic ossification remains largely unclarified. in this project, we administrated Achilles tenotomy (AT) and partial Achilles tenotomy (PAT) to rat models to simulate the varied size of ectopic bone we observed in the clinical courses. Then we applied Data-independent acquisition (DIA) proteomic strategy to identify the proteins and signaling pathways associated with the progress of heterotopic ossification and propagation of the ectopic bone mass.

2021-04-28 | PXD025678 |

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

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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

Tenomodulin prevents trauma-induced heterotopic ossification in tendon

Project description:Tenomodulin prevents trauma-induced heterotopic ossification in tendon

| PRJNA743873 | ENA