한빛사 논문
Min Seuk Kim‡, Yu-Mi Yang‡, Aran Son‡, Yu Shun Tian‡, Syng-Ill Lee‡, Sang Won Kang§, Shmuel Muallem¶ and Dong Min Shin‡,1
‡Department of Oral Biology, Brain Korea 21 Project, Oral Science Research Center, Center for Natural Defense System, Yonsei University College of Dentistry, Seoul 120-752, Korea,
the §Division of Molecular Life Sciences and the Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea, and the ¶Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040
1Corresponding author
Abstract
RANKL (receptor activator of NF-κB ligand) induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca2+ ([Ca2+]i). The [Ca2+]i oscillations activate calcineurin, which activates the transcription factor NFATc1. The pathway by which RANKL induces [Ca2+]i oscillations and osteoclastogenesis is poorly understood. Here we report the discovery of a novel pathway induced by RANKL to cause a long lasting increase in reactive oxygen species (ROS) and [Ca2+]i oscillations that is essential for differentiation of bone marrow-derived monocytes into osteoclasts. The pathway includes RANKL-mediated stimulation of Rac1 to generate ROS, which stimulate phospholipase Cγ1 to evoke [Ca2+]i oscillations by stimulating Ca2+ release from the inositol 1,4,5-trisphosphate pool and STIM1-regulated Ca2+ influx. Induction and activation of the pathway is observed only after 24-h stimulation with RANKL and lasts for at least 3 days. The physiological role of the pathway is demonstrated in mice with deletion of the Peroxiredoxin II gene and results in a mark increase is ROS and, consequently, a decrease in bone density. Moreover, bone marrow-derived monocytes in PrxII−/− primary culture show increased ROS and spontaneous [Ca2+]i oscillations. These findings identify the primary RANKL-stimulated pathway to trigger the late stages of osteoclastogenesis and regulate bone resorption.
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