TGFß reprograms TNF stimulation of macrophages towards osteoclastogenesis [ATAC-seq]

TNF plays a key role in inflammation and bone resorption. However, the mechanisms regulating TNF-mediated osteoclastogenesis remain largely unclear because its direct osteoclastogenic ability is weak. Here, we found that TGFß priming enables TNF to effectively induce osteoclastogenesis from macrophages, independently of the osteoclastogenic action of RANKL. Lack of TGFß signaling in macrophages suppresses inflammatory, but not physiological, osteoclastogenesis and bone resorption in vivo. Mechanistically, TGFß priming reprograms macrophage response to TNF towards osteoclastogenesis by remodeling chromatin accessibility and histone modification. TGFß and TNF induce an unconventional osteoclastogenic program, which includes the suppression of the TNF-induced IRF1-IFNß-IFN stimulated gene (ISG) axis, promotion of IRF8 degradation and B-Myb induction. These mechanisms are present in RA, in which TGFß level is elevated and correlated with osteoclast activity. Our findings identify a function and mechanism of action for TGFß in TNF-mediated inflammatory osteoclastogenesis, and open avenues for selective treatment of inflammatory bone loss. Overall design: Analysis of chromatin accessibility changes in human macrophages with or without TGFb priming in the presence of TNF