AUTHOR=Artsi Hanna , Cohen-Kfir Einav , Shahar Ron , Kalish-Achrai Noga , Lishinsky Natan , Dresner-Pollak Rivka 

TITLE=SIRT1 haplo-insufficiency results in reduced cortical bone thickness, increased porosity and decreased estrogen receptor alpha in bone in adult 129/Sv female mice

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1032262

DOI=10.3389/fendo.2022.1032262

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice.</p></sec><sec><title>Methods</title><p>To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking <italic>Sirt1</italic> exons 5,6,7 (<italic>Sirt1<sup>+/Δ</sup></italic>) and their wild type (WT) counterparts.</p></sec><sec><title>Results</title><p>In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in <italic>Sirt1<sup>+/Δ</sup></italic> compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old <italic>Sirt1<sup>+/Δ</sup></italic> compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between <italic>Sirt1<sup>+/Δ</sup></italic> and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in <italic>Sirt1<sup>+/Δ</sup></italic> compared to WT female mice and was significantly higher in <italic>Sirt1</italic> over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in <italic>Sirt1<sup>+/Δ</sup></italic> versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in <italic>Sirt1<sup>+/Δ</sup></italic> vs. WT mice. No difference in androgen receptor (AR) was detected in bone in <italic>Sirt1<sup>+/Δ</sup></italic> vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton.</p></sec><sec><title>Discussion</title><p>These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.</p></sec>