Activation of Sirtuin1 (Sirt1), an nicotinamide adenine dinucleotide oxidized-dependent deacetylase, by natural or synthetic compounds like resveratrol, SRT2104, or SRT3025 attenuates the loss of bone mass caused by ovariectomy, aging, or unloading in mice. Conversely, Sirt1 deletion in osteoclast progenitors increases osteoclast number and bone resorption. Sirt1 deacetylates forkhead box protein (Fox) O1, FoxO3, and FoxO4, and thereby modulates their activity. FoxOs restrain osteoclastogenesis and bone resorption. Here, we tested the hypothesis that the antiresorptive effects of Sirt1 are mediated by FoxOs. We report that Sirt1 activation by SRT2104 and SRT3025 inhibited murine osteoclast progenitor proliferation and reduced osteoclastogenesis. The effect of Sirt1 stimulators on osteoclastogenesis was abrogated in cells lacking FoxO1, FoxO3, and FoxO4. FoxO1 acetylation was increased by knocking down Sirt1 or addition of receptor activator of nuclear factor kappa-B ligand, the critical cytokine for osteoclast differentiation. Furthermore, acetylation inhibited, whereas deacetylation promoted, FoxO-mediated transcription. SRT3025 increased the expression of the FoxO-target genes catalase and hemeoxygenase-1 (HO-1) in osteoclast progenitors, in a FoxO-dependent manner. HO-1 catabolizes heme and attenuates mitochondrial oxidative phosphorylation and ATP production in macrophages. HO-1 levels were strongly reduced and ATP levels increased by Receptor activator of nuclear factor kappa-B ligand. In contrast, SRT3025 and FoxOs decreased ATP production, and the effect of SRT3025 was mediated by FoxOs. These findings reveal that the antiosteoclastogenic actions of Sirt1 are mediated by FoxOs and result from impaired mitochondria activity. Along with earlier findings that the osteoblastogenic effects of Sirt1 are also mediated by FoxOs, these results establish that the dual antiosteoporotic efficacy of Sirt1 stimulators (ie, decreasing bone resorption and promoting bone formation) is mediated via FoxO deacetylation.

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