Fig. 6

Scheme of FOP pathogenesis and the involvement of NF-κB signalling. FOP is characterized by an autoinflammatory state and immune overactivation in soft tissues, involving immune cells like mast cells, T cells, and monocytes/macrophages. These immune cells create an inflammatory environment, which further activates monocytes/macrophages through the TLR4-related proinflammatory signalling pathway. The ACVR1 R206H mutation enhances the responsiveness of the ALK2 receptor to BMP and activin A, activating the smad signalling pathway and promoting the expression of growth factors, including TGF-β. ACVR1 and TLR4 can also activate TAK1 to promote NF-κB signalling activation, leading to the expression of inflammatory cytokines (TNF-α, IL-1β) and growth factors (VEGF). Inflammasome activation may also contribute to cytokine secretion. Monocyte-secreted molecules like TGF-β and IL-1β recruit MSCs/TSC by activating NF-κB and smad signalling. In MSCs committed to an osteogenic fate, NF-κB and smad synergistically promote osteogenic gene expression (OCN, Sox9, Runx2, Inhibitor of DNA Binding 1 (Id1)). In MSCs committed to a chondrogenic fate, ACVR1 mutation-induced ENPP2 activates mTOR signalling via lysophosphatidic acid (LPA) receptor binding, leading to NF-κB activation and chondrogenesis. Chondrocytes undergo maturation, degradation, and replacement, while osteoblasts differentiate into osteocytes, ultimately resulting in ectopic bone formation (Created with BioRender.com)