RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis

Min Seuk Kim, Yu Mi Yang, Aran Son, Yu Shun Tian, Syng Ill Lee, Sang Won Kang, Shmuel Muallem, Dong Min Shin

Research output: Contribution to journalArticle

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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 [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 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.

Original languageEnglish
Pages (from-to)6913-6921
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number10
DOIs
Publication statusPublished - 2010 Mar 5

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Osteogenesis
Reactive Oxygen Species
Bone
Osteoclasts
Monocytes
Bone Marrow
Peroxiredoxins
Inositol 1,4,5-Trisphosphate
Calcineurin
Bone Resorption
Bone Density
Transcription Factors
Genes
Chemical activation
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kim, Min Seuk ; Yang, Yu Mi ; Son, Aran ; Tian, Yu Shun ; Lee, Syng Ill ; Kang, Sang Won ; Muallem, Shmuel ; Shin, Dong Min. / RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 10. pp. 6913-6921.
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RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis. / Kim, Min Seuk; Yang, Yu Mi; Son, Aran; Tian, Yu Shun; Lee, Syng Ill; Kang, Sang Won; Muallem, Shmuel; Shin, Dong Min.

In: Journal of Biological Chemistry, Vol. 285, No. 10, 05.03.2010, p. 6913-6921.

Research output: Contribution to journalArticle

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AU - Kim, Min Seuk

AU - Yang, Yu Mi

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