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 4

Inactivation of Sirt1 in serotonergic and MAO-A–expressing neurons, but not in the locus coeruleus, increases bone mass in spines of male mice.

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Inactivation of Sirt1 in serotonergic and MAO-A–expressing neurons, but ...
(A) BV/TV (%); (B) N.Ob/T.Ar (/mm2); (C) BFR/BS (μm3/μm2/yr); and (D) Oc.S/BS (%) of 3-, 12-, and 18-month-old male Sirt1Syn–/– mice (3 months: n = 9; 12 months: n = 6; 18 months: n = 5) versus Sirt1COIN/COIN controls (3 months: n = 8; 12 months: n = 5; 18 months: n = 7). (E) Representative images of spines from 3-, 12-, and 18-month-old male Sirt1Syn–/– mice versus Sirt1COIN/COIN controls, stained with von Kossa. (F) BV/TV (%); (G) N.Ob/T.Ar (/mm2); (H) BFR/BS (μm3/μm2/yr); and (I) Oc.S/BS (%) of 3-, 12-, and 18-month-old male Sirt1Sert–/– mice (3 months: n = 8; 12 months: n = 8; 18 months: n = 9) versus Sirt1COIN/COIN controls (3 months: n = 6; 12 months: n = 5; 18 months: n = 8). (J) Representative images of spines from 3-, 12-, and 18-month-old male Sirt1Sert–/– mice versus Sirt1COIN/COIN controls stained with von Kossa. (K) BV/TV (%); (L) N.Ob/T.Ar (/mm2); (M) BFR/BS (μm3/μm2/yr); and (N) Oc.S/BS (%) of 3- and 12- month-old male Sirt1Dbh–/– mice (3 months: n = 5; 12 months: n = 7) versus Sirt1COIN/COIN controls (3 months: n = 5; 12 months: n = 5). (O) Representative images of spines from 3- and 12-month-old male Sirt1Dbh–/– mice versus Sirt1COIN/COIN controls stained with von Kossa. Data are represented as mean ± SEM. *P < 0.05 versus Sirt1COIN/COIN by Student’s t test.