Silent information regulator (Sir)T1 inhibits NF-[kappa]B signaling to maintain normal skeletal remodeling

Silent information regulator T1 (SirT1) is linked to longevity and negatively controls NF-[kappa]B signaling, a crucial mediator of survival and regulator of both osteoclasts and osteoblasts. Here we show that NF-[kappa]B 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 Sirtflox/flox mice crossed to lysozyme M-cre and the 2.3kb 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-[kappa]B by increasing acetylation of Lysine 310. Importantly, this increase in osteoclastogenesis was blocked by pharmacological inhibition of NF-[kappa]B. In osteoblasts, decreased SirT1 reduced osteoblast differentiation, which could also be rescued by inhibition of NF-[kappa]B. In further support of the critical role of NF-[kappa]B signaling in bone remodeling, elevated NF-[kappa]B activity in I[kappa]B[alpha]+/- 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-[kappa]B and bone cell differentiation. © 2013 American Society for Bone and Mineral Research. [PUBLICATION ABSTRACT]