Activin-a induces early differential gene expression exclusively in periodontal ligament fibroblasts from fibrodysplasia ossificans progressiva patients

Ton Schoenmaker*, Michal Mokry, Dimitra Micha, Coen Netelenbos, Nathalie Bravenboer, Marjolein Gilijamse, E. Marelise W. Eekhoff, Teun J. De Vries

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown that capturing Activin-A protects against heterotopic ossification in animal models, the exact underlying mechanisms at the gene expression level causing ACVR1 R206H-mediated ossifications and progression are thus far unknown. We investigated the early transcriptomic changes induced by Activin-A of healthy control and patient-derived periodontal ligament fibroblasts (PLF) isolated from extracted teeth by RNA sequencing analysis. To study early differences in response to Activin-A, periodontal ligament fibroblasts from six control teeth and from six FOP patient teeth were cultured for 24 h without and with 50 ng/mL Activin-A and analyzed with RNA sequencing. Pathway analysis on genes upregulated by Activin-A in FOP cells showed an association with pathways involved in, among others, Activin, TGFβ, and BMP signaling. Differential gene expression induced by Activin-A was exclusively seen in the FOP cells. Median centered supervised gene expression analysis showed distinct clusters of up- and downregulated genes in the FOP cultures after stimulation with Activin-A. The upregulated genes with high fold changes like SHOC2, TTC1, PAPSS2, DOCK7, and LOX are all associated with bone metabolism. Our open-ended approach to investigating the early effect of Activin-A on gene expression in control and FOP PLF shows that the molecule exclusively induces differential gene expression in FOP cells and not in control cells.

Original languageEnglish
Article number629
Pages (from-to)1-16
Number of pages16
Issue number6
Early online date1 Jun 2021
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
Funding: This study was funded by the IFOPA FOP Competitive Research Grant.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Activin-A
  • Fibrodysplasia ossificans progressiva
  • Heterotopic ossification
  • Periodontal ligament fibroblasts
  • RNA sequencing


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