title: RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis.
abstract: RANKL (receptor activator of NF-kappaB 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 Ca(2+) ([Ca(2+)](i)). The [Ca(2+)](i) oscillations activate calcineurin, which activates the transcription factor NFATc1. The pathway by which RANKL induces [Ca(2+)](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 [Ca(2+)](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 Cgamma1 to evoke [Ca(2+)](i) oscillations by stimulating Ca(2+) release from the inositol 1,4,5-trisphosphate pool and STIM1-regulated Ca(2+) 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 [Ca(2+)](i) oscillations. These findings identify the primary RANKL-stimulated pathway to trigger the late stages of osteoclastogenesis and regulate bone resorption.
authors.affiliation: 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.
authors.forename: Min Seuk
authors.initials: MS
authors.lastname: Kim
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Yang
authors.forename: Aran
authors.initials: A
authors.lastname: Son
authors.forename: Yu Shun
authors.initials: YS
authors.lastname: Tian
authors.forename: Syng-Ill
authors.initials: SI
authors.lastname: Lee
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D053245:RANK Ligand; D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; D051966:Phospholipase C gamma; D020830:rac1 GTP-Binding Protein