Transcriptomic Differences Underlying the Activin-A Induced Large Osteoclast Formation in Both Healthy Control and Fibrodysplasia Ossificans Progressiva Osteoclasts

Ton Schoenmaker*, Joy Zwaak, Bruno G. Loos, Richard Volckmann, Jan Koster, E. Marelise W. Eekhoff, Teun J. de Vries*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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 languageEnglish
Article number6822
Pages (from-to)1-22
Number of pages22
JournalInternational Journal of Molecular Sciences
Volume24
Issue number7
DOIs
Publication statusPublished - 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

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