IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions

Cytokines secreted by T cells play a pivotal role in inflammatory bone destruction. Tumor necrosis factor-alpha (TNF-alpha) is a major proinflammatory cytokine produced by macrophages following T cell activation, and directly promotes osteoclast differentiation resulting in accelerated bone resorption. Interferon-gamma (IFN-gamma) attenuates RANKL-initiated cellular signals through osteoclast formation and counterbalances aberrant bone resorption. With respect to this crosstalk during osteoclastogenesis, the direct interruption of IFN-gamma in TNF-alpha-induced osteoclast formation still requires elucidation. We have demonstrated that IFN-gamma directly inhibits osteoclastogenesis induced by INF-alpha stimulation and accelerates apoptosis mediated by Fas/Fas ligand signals. There were a decreased number of osteoclasts and reduced mRNA levels encoding Nfatc1 in cultured bone marrow macrophages. Apoptotic responses of cultured cells were observed, with accelerated nuclear fragmentation in osteoclast precursor cells and increased FasL mRNA levels in bone marrow cells stimulated with TNF-alpha evident. IFN-gamma reduced the level of osteoclastogenesis in response to TNF-alpha treatment in vivo. IFN-gamma inhibited TNF-alpha-induced osteoclastogenesis in mice with T cells that had been exposed to anti-CD4 and -CD8 antibodies. These results provide evidence that IFN-gamma directly inhibits osteoclastogenesis and induces cells apoptosis by Fas/FasL signals, leading to the indirect regulation of bone resorption, which is required for protective roles in bone destruction at an inflammation site. (C) 2011 Elsevier B.V. All rights reserved.