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.; Gomez-Suarez, N.; Lopez, A. D.; Farfan, N.; Bekedam, F.; Sampadi, B.; Rotman, S.; Lopez, D. R.; Marquez, J. B.; Arendzen, C.; Freund, C.; Veelen, P. v.; Valldeperas, A. L.; Man, F. d.; Ventura, F.; Goumans, M.-J.; Sanchez-Duffhues, G.

doi:10.1101/2025.01.21.634061

bioRxiv · 10.1101/2025.01.21.634061

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.·Gomez-Suarez, N.·Lopez, A. D.·Farfan, N.·Bekedam, F.·Sampadi, B.·Rotman, S.·Lopez, D. R.·Marquez, J. B.·Arendzen, C.·Freund, C.·Veelen, P. v.·Valldeperas, A. L.·Man, F. d.·Ventura, F.·Goumans, M.-J.·Sanchez-Duffhues, G.

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Abstract

BackgroundFibrodysplasia 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. MethodsWe performed phosphoproteomics, transcriptomics and biochemical analyses in mesenchymal cells (MSCs) overexpressing wild-type ALK2WT or mutant ALK2R206H 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. ResultsMulti-omics analyses revealed previously unrecognized signaling networks in ALK2R206H 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. ConclusionThis 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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Wits, M., Gomez-Suarez, N., Lopez, A. D., Farfan, N., Bekedam, F., Sampadi, B., Rotman, S., Lopez, D. R., Marquez, J. B., Arendzen, C., Freund, C., Veelen, P. v., Valldeperas, A. L., Man, F. d., Ventura, F., Goumans, M.-J., Sanchez-Duffhues, G.. 2025-01-21. 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. https://doi.org/10.1101/2025.01.21.634061

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