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.
Show 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.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Basigin Links Altered Skeletal Stem Cell Lineage Dynamics with Glucocorticoid-induced Bone Loss and Impaired Angiogenesis 94%
- Nerve Growth Factor Receptor Limits Inflammation to Promote Remodeling and Repair of Osteoarthritic Joints 94%
- Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow 94%
Similar papers in this journal
- Mesenchymal stromal cell chondrogenesis under ALK1/2/3-specific BMP inhibition: A revision of the prohypertrophic signalling network concept 95%
- Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated Schwann cell proliferation in human. 95%
- Autologous iPSC- and MSC-derived Chondrocyte Implants for Cartilage Repair in a Miniature Pig Model 93%
Similar papers in this journal
- SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation 95%
- Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis 94%
- Antigen Presentation-Independent Reciprocal Immune Modulation by HLA-DRB1 Allelic Epitopes that Associate with Autoimmune Disease Risk or Protection 94%
Similar papers in this journal
- Transcriptional plasticity of stromal cells amplifies their differentiation efficiency in vitro 94%
- PTX3 Governs Fibroblast-Epithelial Dynamics in Lung Injury and Repair 94%
- Periosteum-derived podoplanin-expressing stromal cells regulate nascent vascularization during epiphyseal marrow development 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.