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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 publication

DOI

10.1002/jbmr.1824

Type

Journal article

Journal

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Publication Date

04/2013

Volume

28

Pages

960 - 969

Addresses

Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. James.Edwards@ndorms.ox.ac.uk

Keywords

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