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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE233843 | GEO | 2023/07/01

REPOSITORIES: GEO

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

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

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Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

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| PRJNA312581 | ENA

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2015-05-12 | E-GEOD-68766 | biostudies-arrayexpress

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