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January 21st, 2025
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Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC)
molecular biology
biorxiv

Multi-omics reveals global signaling rewiring and identifies Activin A-induced dysregulation of FOS/Activator Protein 1 as a novel target in Fibrodysplasia ossificans progressiva

Wits, M.Open in Google Scholar•Gomez-Suarez, N.Open in Google Scholar•Lopez, A. D.Open in Google Scholar•Farfan, N.Open in Google Scholar•Bekedam, F.Open in Google Scholar•Sampadi, B.Open in Google Scholar•Rotman, S.Open in Google Scholar•Lopez, D. R.Open in Google Scholar•Marquez, J. B.Open in Google Scholar•Arendzen, C.Open in Google Scholaret al.

Background: Fibrodysplasia ossificans progressiva (FOP) is caused by an activating mutation (p.R206H) in the type I BMP receptor ALK2, leading to heterotopic ossification (HO) in soft connective tissues. While aberrant Activin A-induced SMAD signaling is central in FOP pathogenesis, global signaling alterations remain poorly understood. Methods: We performed phosphoproteomics, transcriptomics and biochemical analyses in mesenchymal cells (MSCs) overexpressing wild-type ALK2-WT or mutant ALK2-R206H receptors and in induced-MSCs derived from FOP patient iPSCs. Findings were validated in vivo using FOP-like mouse models and in vitro via pharmacological interventions. Results: Multi-omics analyses revealed previously unrecognized signaling networks in ALK2-R206H cells, including enhanced MAPK, mTOR, RUNX2 and RHO-mediated mechanotransduction pathways. Notably, we identified dysregulated Activator Protein-1 (AP-1) expression and function as a novel contributor to FOP. AP-1 factors were highly enriched in HO lesions in FOP-like animals. Pharmacological inhibition of AP-1 significantly reduced osteochondrogenic differentiation in vitro. Conclusion: This study highlights global signaling dysregulation in FOP and identifies AP-1 as a critical driver and potential therapeutic target for FOP.

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