Silent information regulator (Sir)T1 inhibits NF-κB signaling to maintain normal skeletal remodeling

James R. Edwards, Daniel S. Perrien, Nicole Fleming, Jeffry S. Nyman, Koichiro Ono, Linda Connelly, Megan M. Moore, Seint T. Lwin, Fiona E. Yull, Gregory R. Mundy, Florent Elefteriou

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Silent information regulator T1 (SirT1) is linked to longevity and negatively controls NF-κB signaling, a crucial mediator of survival and regulator of both osteoclasts and osteoblasts. Here we show that NF-κB repression by SirT1 in both osteoclasts and osteoblasts is necessary for proper bone remodeling and may contribute to the mechanisms linking aging and bone loss. Osteoclast- or osteoblast-specific SirT1 deletion using the Sirt flox/flox mice crossed to lysozyme M-cre and the 2.3 kb col1a1-cre transgenic mice, respectively, resulted in decreased bone mass caused by increased resorption and reduced bone formation. In osteoclasts, lack of SirT1 promoted osteoclastogenesis in vitro and activated NF-κB by increasing acetylation of Lysine 310. Importantly, this increase in osteoclastogenesis was blocked by pharmacological inhibition of NF-κB. In osteoblasts, decreased SirT1 reduced osteoblast differentiation, which could also be rescued by inhibition of NF-κB. In further support of the critical role of NF-κB signaling in bone remodeling, elevated NF-κB activity in IκBα+/- mice uncoupled bone resorption and formation, leading to reduced bone mass. These findings support the notion that SirT1 is a genetic determinant of bone mass, acting in a cell-autonomous manner in both osteoblasts and osteoclasts, through control of NF-κB and bone cell differentiation.

Original languageEnglish (US)
Pages (from-to)960-969
Number of pages10
JournalJournal of Bone and Mineral Research
Volume28
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Keywords

  • aging
  • NF-κB
  • osteoblast
  • osteoclast
  • SirT1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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