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

Edwards JR, Perrien DS, Fleming N, Nyman JS, Ono K, Connelly L, Moore MM, Lwin ST, Yull FE, Mundy GR, Elefteriou F
J Bone Miner Res. 2013 28 (4): 960-9

PMID: 23172686 · DOI:10.1002/jbmr.1824

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.

Copyright © 2013 American Society for Bone and Mineral Research.

MeSH Terms (17)

Acetylation Aging Animals Bone and Bones Bone Remodeling Gene Deletion Gene Knockdown Techniques I-kappa B Proteins Mice NF-kappa B NF-KappaB Inhibitor alpha Organ Size Organ Specificity Osteoblasts Osteoclasts Signal Transduction Sirtuin 1

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