Sirtuin 6 in preosteoclasts suppresses age- and estrogen deficiency-related bone loss by stabilizing estrogen receptor α.

Cell Death and Differentiation
Young Jae MoonByung-Hyun Park

Abstract

Emerging evidence indicates that estrogen receptor (ER) α is an important modulator of bone homeostasis, which occurs partly by promoting osteoclast apoptosis. Sirtuin 6 (Sirt6) is an anti-aging molecule, and its deficiency in mice results in skeletal malformations associated with progeroid features. However, the effects of Sirt6 on ERα function in osteoclasts, and thus on aging- or estrogen deficiency-induced bone loss, have not been studied. Here, we show that myeloid-specific deletion of Sirt6 led to decreased ERα protein level and apoptotic cell death in preosteoclasts. Consequently, myeloid Sirt6 KO mice showed aggravated cancellous bone loss both with aging and following an ovariectomy compared to wild-type littermates. In contrast, Sirt6 transgenic mice were protected from ovariectomy-induced bone loss. Mechanistically, Sirt6 deacetylated ERα protein to prevent its proteasomal degradation, in which lysine 171 and lysine 299 were critical residues. Sirt6-mediated ERα stabilization promoted transcription of Fas ligand in preosteoclasts, resulting in apoptosis of osteoclasts. Finally, the level of Sirt6 in human preosteoclasts was correlated positively with bone density and ERα but negatively with age. In conclusion, our re...Continue Reading

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Citations

Oct 9, 2019·Cells·Chun Wang, Gabriel Mbalaviele
Sep 22, 2019·Experimental & Molecular Medicine·In Hyuk BangByung-Hyun Park
Nov 5, 2020·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Zhongkai ZhangJung Ryul Kim
Mar 27, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chiaki YamadaAlexandru Movila
Jun 5, 2021·Nature Communications·Fujun JinXiaogang Wang
May 30, 2021·The Journal of Allergy and Clinical Immunology·Hyun-Young JangByung-Hyun Park
Jul 31, 2021·Stem Cells International·Qinglu TianYachuan Zhou
Aug 8, 2021·British Journal of Pharmacology·Lihua HaoByung-Hyun Park

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Methods Mentioned

BETA
acetylation
hormone replacement therapy
X-ray
ELISA
ubiquitination
transfection
co-immunoprecipitation assay
co-immunoprecipitation
transgenic

Software Mentioned

GraphPad Prism

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis