Fig. 7

Schematic illustration of therapeutics of endochondral ossification and FOP targeting NF-κB signalling. A Endochondral ossification: therapeutics based on inflammatory responses. Metformin could both activate the SIRT1 and AMPK pathways to inhibit NF-κB-P65 activity to block inflammatory cytokine secretion, therefore repressing their capacity for infiltration and activation and other activities. Quercetin and ECF can activate AMPK to inhibit the transcriptional actions of NF-κB-dependent inflammatory genes. B FOP: therapy based on inflammatory responses and MSC/TSC differentiation. During inflammation, the ACVR1 R206H mutation exuberantly stimulates smad1/5/9 phosphorylation. Furthermore, smad4 is recruited to form a complex with smad1/5/9, which can interact with NF-κB signalling. FOP patients were found to show hyperreactivity of TLR4, which may also spark TAK1 and further NF-κB translocation to evoke synergistic roles with smad signalling. Interestingly, ACVR1-mediated signalling is also able to induce TAK1 activation. As a RARγ agonist, palovarotene interferes with smad complex formation to block inflammatory responses and MSC differentiation. Furthermore, in MSCs/TSC (tendon stem cell), it seems that palovarotene may also block the downstream transcriptional target of both NF-κB and smad, including OCN, Sox9, Runx2 and Id1, induced by macrophage-secreted molecules, including TGF-β and IL-1β, to further alleviate FOP (Created with BioRender.com)