TRANCE-induced Osteoclast Differentiation Requires Production of Reactive Oxygen Species

다국어 초록 (Multilingual Abstract)

TRANCE, a TNF family member, is a key osteoclast differentiation/activation factor essential for bone remodeling. However, molecular mechanisms by which TRANCE activates various downstream kinases, leading to osteoclastogenesis remain to be elucidated. Here, we demonstrate that TRANCE stimulation of both bone marrow monocytes and RAW 264.7 cells, a monocytic cell line, transiently increased the intracellular concentration of reactive oxygen species(ROS) through a signaling complex involving TRAF6, c-Src, and PI3-kinase. TRANCE-induced osteoclast differentiation of bone marrow cells was inhibited when ROS production was prevented by PI3-kinase inhibitors and a flavoprotein inhibitor, diphenylene iodonium. The expression of dominant negative form of TRAF6 and treatment of PI3-kinase inhibitors specifically inhibited TRANCE-induced p38 MAP kinase activation but not ERK and JNK activation, suggesting TRANCE generates ROS through TRAF6-PI3-kinase-dependent pathway. ROS may, in turn, activate p38 MAP kinase, leading to osteoclast differentiation.