Abstract
Fibrodysplasia Ossificans Progressiva (FOP) is a very rare genetic disease characterized by progressive heterotopic ossification (HO) of soft tissues, leading to immobility and premature death. FOP is caused by a mutation in the Activin receptor Type 1 (ACVR1) gene, resulting in altered responsiveness to Activin-A. We recently revealed that Activin-A induces fewer, but larger and more active, osteoclasts regardless of the presence of the mutated ACVR1 receptor. The underlying mechanism of Activin-A-induced changes in osteoclastogenesis at the gene expression level remains unknown. Transcriptomic changes induced by Activin-A during osteoclast formation from healthy controls and patient-derived CD14-positive monocytes were studied using RNA sequencing. CD14-positive monocytes from six FOP patients and six age- and sex-matched healthy controls were differentiated into osteoclasts in the absence or presence of Activin-A. RNA samples were isolated after 14 days of culturing and analyzed by RNA sequencing. Non-supervised principal component analysis (PCA) showed that samples from the same culture conditions (e.g., without or with Activin-A) tended to cluster, indicating that the variability induced by Activin-A treatment was larger than the variability between the control and FOP samples. RNA sequencing analysis revealed 1480 differentially expressed genes induced by Activin-A in healthy control and FOP osteoclasts with p(adj) < 0.01 and a Log2 fold change of ≥±2. Pathway and gene ontology enrichment analysis revealed several significantly enriched pathways for genes upregulated by Activin-A that could be linked to the differentiation or function of osteoclasts, cell fusion or inflammation. Our data showed that Activin-A has a substantial effect on gene expression during osteoclast formation and that this effect occurred regardless of the presence of the mutated ACVR1 receptor causing FOP.
Original language | English |
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Article number | 6822 |
Pages (from-to) | 1-22 |
Number of pages | 22 |
Journal | International Journal of Molecular Sciences |
Volume | 24 |
Issue number | 7 |
DOIs | |
Publication status | Published - 1 Apr 2023 |
Bibliographical note
This article belongs to the Special Issue: Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside.Funding Information:
This work was funded in part by research grant 03082020 from the Friends of Dutch FOP Foundation.
Publisher Copyright:
© 2023 by the authors.
Funding
This work was funded in part by research grant 03082020 from the Friends of Dutch FOP Foundation.
Keywords
- Activin-A
- cell size
- fibrodysplasia ossificans progressiva
- osteoclast
- RNAseq