Fig. 3.

Schematic of NF-κB signalling in the communication between active macrophages and MSCs. A General process of HO formation starting from macrophage activation or pyroptosis and MSC activation or senescence leading to ectopic bone formation. B Communication between pyroptotic macrophages and TDSCs (MSCs). In macrophages, inflammatory cytokines bind to TLR4, activating IKK and allowing NF-κB to promote NLRP3 and pro-IL-1β gene expression. HMGB1 is packaged in the Golgi and, along with IL-1β, is released in extracellular vesicles. HMGB1-TLR9 complex forms on TDSCs, activating IκB-NF-κB, initiating TDSC osteogenesis. C Communication between active macrophages and MSCs. Similar to (B), NF-κB-dependent gene expression leads to inflammatory cytokine secretion. IL-1β and BMP2/6 activate PI3K/AKT signalling, promoting P65 translocation into the nucleus for chondrogenic gene expression. BMP and TGF-β induce smad activity for chondrogenesis and osteogenesis-permissive gene expression through smad1/5/8 or smad2/3 and smad4 complex formation (Created with BioRender.com)