| First Author | Edwards JR | Year | 2013 |
| Journal | J Bone Miner Res | Volume | 28 |
| Issue | 4 | Pages | 960-9 |
| PubMed ID | 23172686 | Mgi Jnum | J:210142 |
| Mgi Id | MGI:5569603 | Doi | 10.1002/jbmr.1824 |
| Citation | Edwards JR, et al. (2013) Silent information regulator (Sir)T1 inhibits NF-kappaB signaling to maintain normal skeletal remodeling. J Bone Miner Res 28(4):960-9 |
| abstractText | Silent information regulator T1 (SirT1) is linked to longevity and negatively controls NF-kappaB signaling, a crucial mediator of survival and regulator of both osteoclasts and osteoblasts. Here we show that NF-kappaB 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-kappaB by increasing acetylation of Lysine 310. Importantly, this increase in osteoclastogenesis was blocked by pharmacological inhibition of NF-kappaB. In osteoblasts, decreased SirT1 reduced osteoblast differentiation, which could also be rescued by inhibition of NF-kappaB. In further support of the critical role of NF-kappaB signaling in bone remodeling, elevated NF-kappaB activity in IkappaBalpha(+/-) 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-kappaB and bone cell differentiation. |
