title: Silent information regulator (Sir)T1 inhibits NF-κB signaling to maintain normal skeletal remodeling.
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.
authors.affiliation: Vanderbilt Center for Bone Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. James.Edwards@ndorms.ox.ac.uk
authors.forename: James R
authors.initials: JR
authors.lastname: Edwards
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Perrien
authors.forename: Nicole
authors.initials: N
authors.lastname: Fleming
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Linda
authors.initials: L
authors.lastname: Connelly
authors.forename: Megan M
authors.initials: MM
authors.lastname: Moore
authors.forename: Seint T
authors.initials: ST
authors.lastname: Lwin
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Mundy
authors.forename: Florent
authors.initials: F
authors.lastname: Elefteriou
mesh_terms: D000107:Acetylation; D000375:Aging / Q000378:metabolism; D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000033:anatomy & histology / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009929:Organ Size; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1