TGF-beta(1) and IFN-gamma direct macrophage activation by TNF-alpha to osteoclastic or cytocidal phenotype

TNF-related activation-induced cytokine (TRANCE; also called receptor activ ator of NF-kappaB ligand (RANKL), osteoclast differentiation factor (ODF), osteoprotegerin ligand (OPGL), and TNFSF11) induces the differentiation of progenitors of the mononuclear phagocyte lineage into osteoclasts in the pr esence of M-CSF, Surprisingly, in view of its potent ability to induce infl ammation and activate macrophage cytocidal function, TNF-alpha has also bee n found to induce osteoclast-like cells in vitro under similar conditions. This raises questions concerning both the nature of osteoclasts and the mec hanism of lineage choice in mononuclear phagocytes. We found that, as with TRANCE, the macrophage deactivator TGF-beta (1) strongly promoted TNF-alpha -induced osteoclast-like cell formation from immature bone marrow macropha ges. This was abolished by IFN-gamma. However, TRANCE did not share the abi lity of TNF-alpha to activate NO production or heighten respiratory burst p otential by macrophages, or induce inflammation on s.c. injection into mice . This suggests that TGF-beta (1) promotes osteoclast formation not only by inhibiting cytocidal behavior, but also by actively directing TNF-alpha ac tivation of precursors toward osteoclasts, The osteoclast appears to be an equivalent, alternative destiny for precursors to that of cytocidal macroph age, and may represent an activated variant of scavenger macrophage.