Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

Background: Sirt1 activity, like osteoblast number and bone mass, declines with age. Results: Mice with Sirt1 deletion in osteoprogenitor cells have low cortical bone mass due to decreased bone formation resulting from increased -catenin sequestration by FoxOs. Conclusion: Sirt1 increases Wnt signaling and bone formation by a mechanism involving FoxOs. Significance: Sirt1 in osteoprogenitor cells could be a therapeutic target for osteoporosis. A decline of the levels and activity of Sirtuin1 (Sirt1), a NAD(+) class III histone deacetylase, with age contributes to the development of several diseases including type 2 diabetes, neurodegeneration, inflammation, and cancer. The anti-aging effects of Sirt1 evidently result from the deacetylation of many transcription factors and co-factors including members of the Forkhead box O (FoxO) family and -catenin. Wnt/-catenin is indispensable for osteoblast generation. FoxOs, on the other hand, sequester -catenin and inhibit osteoprogenitor proliferation. Here, we have deleted Sirt1 in osteoprogenitors expressing Osterix1 (Osx1)-Cre and their descendants. Sirt1(Osx1) mice had lower cortical thickness in femora and vertebrae because of reduced bone formation at the endocortical surface. In line with this, osteoprogenitor cell cultures from the Sirt1(Osx1) mice exhibited lower alkaline phosphatase activity and mineralization, as well as decreased proliferation and increased apoptosis. These changes were associated with decreased Wnt/-catenin signaling and expression of cyclin D1 and resulted from increased binding of FoxOs to -catenin. These findings demonstrate that Sirt1-induced deacetylation of FoxOs unleashes Wnt signaling. A decline in Sirt1 activity in osteoblast progenitors with aging may, therefore, contribute to the age-related loss of bone mass. Together with evidence that Sirt1 activators increase bone mass in aged mice, our results also suggest that Sirt1 could be a therapeutic target for osteoporosis.