A neuronal action of sirtuin 1 suppresses bone mass in young and aging mice
Na Luo, … , J. John Mann, Stavroula Kousteni
Na Luo, … , J. John Mann, Stavroula Kousteni
Published October 4, 2022
Citation Information: J Clin Invest. 2022;132(23):e152868. https://doi.org/10.1172/JCI152868.
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Research Article Bone biology Neuroscience

A neuronal action of sirtuin 1 suppresses bone mass in young and aging mice

Abstract

The various functions of the skeleton are influenced by extracellular cues, hormones, and neurotransmitters. One type of neuronal regulation favors bone mass accrual by inhibiting sympathetic nervous system (SNS) activity. This observation raises questions about the transcriptional mechanisms regulating catecholamine synthesis. Using a combination of genetic and pharmacological studies, we found that the histone deacetylase sirtuin 1 (SIRT1) is a transcriptional modulator of the neuronal control of bone mass. Neuronal SIRT1 reduced bone mass by increasing SNS signaling. SIRT1 did so by increasing expression of monoamine oxidase A (MAO-A), a SIRT1 target that reduces brain serotonin levels by inducing its catabolism and by suppressing tryptophan hydroxylase 2 (Tph2) expression and serotonin synthesis in the brain stem. SIRT1 upregulated brain catecholamine synthesis indirectly through serotonin, but did not directly affect dopamine β hydroxylase (Dbh) expression in the locus coeruleus. These results help us to understand skeletal changes associated with selective serotonin reuptake inhibitors (SSRIs) and may have implications for treating skeletal and metabolic diseases.

Authors

Na Luo, Ioanna Mosialou, Mattia Capulli, Brygida Bisikirska, Chyuan-Sheng Lin, Yung-yu Huang, Peter T. Shyu, X. Edward Guo, Aris Economides, J. John Mann, Stavroula Kousteni

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Figure 1

Increased sympathetic tone and decreased bone mass in TgSirt1 mice.

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Increased sympathetic tone and decreased bone mass in TgSirt1 mice. (A) ...
(A) Number of osteoblasts per trabecular area (N.Ob/T.Ar) (/mm2); (B) osteoclast surface per bone surface (Oc.S/BS) (%); (C) bone volume over tissue volume (BV/TV) (%); and (D) BFR/BS (μm3/μm2/yr) of TgSirt1 mice (1.5 months: n = 6; 3 months: n = 8; 12 months: n = 5) versus WT controls (1.5 months: n = 3; 3 months: n = 6; 12 months: n = 5) at 1.5, 3, and 12 months of age. (E) Representative images of spines from TgSirt1 and WT control mice stained with von Kossa. (F) Relative expression levels of osteoblast and osteoclast differentiation marker genes in long bones of 3-month-old TgSirt1 mice (n = 6) versus WT controls (n = 6). (G) Urine epinephrine levels in 3-month-old TgSirt1 mice (n = 7) versus WT controls (n = 3). (H) Urine NE levels in 3-month-old TgSirt1 mice (n = 7) versus WT controls (n = 3). (I) Ucp1 expression levels in BAT of 3-month-old TgSirt1 mice (n = 6) versus WT controls (n = 6). (J) Relative expression levels of sympathetic tone target genes in long bones of 3-month-old TgSirt1 mice (n = 6) versus WT controls (n = 6). (K) N.Ob/T.Ar (/mm2); (L) Oc.S/BS (%); (M) BV/TV (%); and (N) BFR/BS (μm3/μm2/yr) of 3-month-old TgSirt1 and WT mice treated with propranolol (WT: n = 5; TgSirt1: n = 5; WT/propranolol: n = 5; TgSirt1/propranolol: n = 5). (O) Representative images of spines from 3-month-old TgSirt1 and WT mice treated with propranolol stained with von Kossa. Data are represented as mean ± SEM. (A–J) *P < 0.05, TgSirt1 versus WT by Student’s t test. (K–N) *P < 0.05, TgSirt1 treated with propranolol versus TgSirt1 by 1-way ANOVA.