Deletion of Sirt3 Increases Bone Mass and Alleviates Estrogen Deficiency-induced Bone Loss Through Suppressing Osteoclast Activity
Refereed conference paper presented and published in conference proceedings


摘要Purpose: Sirt3 is a NAD+-dependent deacetylase and plays important roles in mitochondrial
function and energy homeostasis. Osteoclasts (OC) consist of large amounts of mitochondria owing
to high energy demand for bone-resorption activity. Previous study demonstrated the regulatory
effect of Sirt3 on OC formation in vitro only. In this study, we aimed to study the biological function
of Sirt3 in OC activity in aging and ovariectomy (OVX)-induced osteoporosis mice models.
Methods: First, Sirt3 expression was investigated during OC differentiation in vitro by using primary
bone marrow-derived macrophages (BMM), and in fresh bone tissue and bone marrow cells collected
from ovariectomized mice and sham group. Next, we knockdown Sirt3 expression in RAW264.7 cell
line to determine its effect on osteoclast differentiation. Moreover, female mice with global deletion
(KO) of Sirt3 gene were used for the characterization of bone phenotypes at different ages (5 weeks,
3 months and 6 months old). Finally, the impact of Sirt3 deficiency on OVX-induced bone loss was
investigated. Micro-CT analysis was used to evaluate trabecular and cortical parameters. Tartrateresistant acid phosphatase (TRAP) staining and serum biochemistry of TRACP-5b was used to
evaluate osteoclast activity. Two-tailed Student’s t test, one-way ANOVA and two-way ANOVA tests
following post hoc Bonferroni’s correction test were used for statistical analysis.
Results: Cellular study demonstrated that Sirt3 mRNA level was greatly increased during the
differentiation of BMMs to mature OCs and inhibition of Sirt3 significantly decreased
osteoclastogenesis. Sirt3 mRNA in bone tissue and bone marrow cells was also significantly
increased following OVX in wildtype (WT) mice. Compared to WT mice, Sirt3 deletion in KO mice
resulted in increased femoral cortical thickness and higher trabecular bone mineral density in femur,
which could be attributed to lower OC activity following Sirt3 deletion as indicated by suppressed
osteoclastogenic differentiation and decreased serum level of TRACP-5b level. Finally, we observed
OVX markedly depleted bone mass in WT mice but this decline was less obvious in Sirt3 KO mice.
TRAP staining and ELISA assay showed that OC activities was markedly enhanced in the WT OVX
group when compared to WT sham group, while no significant difference was observed in bone
resorption parameters between Sirt3 KO sham group and Sirt3 KO OVX group.
Conclusion: Sirt3 has important roles in the bone homeostasis and estrogen deficiency-induced bone
loss by modulating OC activity, suggesting that inhibiting Sirt3 and its downstream targets might be
novel therapeutic targets to modulate osteoresorptive disorders.
著者Qiangqiang Li, Haixing Wang, Jiajun Zhang, Alice PS Kong, Jack CY Cheng, Wayne YW Lee
會議名稱ASBMR Annual Meeting 2020
會議地點Virtual event

上次更新時間 2021-04-01 於 10:04