Abstract
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.
Highlights
Introduction distributed under the terms and Fibrodysplasia ossificans progressiva (FOP) is a rare, one-in-two-million-occurring, autosomal dominant genetic disease characterized by progressive heterotopic bone formation (HO) where especially muscles, tendons, and ligaments are converted into bone [1,2,3]
Initial gene expression analysis without false discovery rate correction showed that, when using a p-value cutoff of p < 0.01, 131 genes are differentially expressed in Fibrodysplasia Ossificans Progressiva (FOP) cells as compared to 46 genes in the control cells
Pathway analysis of these genes using GeneMania shows an association with pathways involved in Activin, bone morphogenetic protein (BMP), and TGFβ signaling only in the FOP cells
Summary
Fibrodysplasia ossificans progressiva (FOP) is a rare, one-in-two-million-occurring, autosomal dominant genetic disease characterized by progressive heterotopic bone formation (HO) where especially muscles, tendons, and ligaments are converted into bone [1,2,3]. Biomedicines 2021, 9, 629 flare up, during inflammation, after injury, or even spontaneously. HO is more progressive than in others, and episodes exist with complete absence of HO formation [4]. Because of these differences in clinical manifestations, cell biological approaches that can shed light on the biochemical events that precede heterotopic ossification are of great importance as a prelude to therapy. The causative mutation in the gene encoding the Activin Receptor Type I receptor (ACVR1) was identified by the group of
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