Dataset Information

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

ABSTRACT: Emerging evidence indicates that estrogen receptor (ER) ? 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 ER? 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 ER? 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 ER? protein to prevent its proteasomal degradation, in which lysine 171 and lysine 299 were critical residues. Sirt6-mediated ER? 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 ER? but negatively with age. In conclusion, our results suggest that deacetylation and upregulation of ER? by Sirt6 in preosteoclasts prevent bone loss by inhibiting osteoclast-mediated bone resorption. Activation of Sirt6 in preosteoclasts may provide a new therapeutic approach to attenuate osteoporosis in older or postmenopausal patients.

SUBMITTER: Moon YJ

PROVIDER: S-EPMC6889517 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Moon Young Jae YJ Zhang Zhongkai Z Bang In Hyuk IH Kwon Oh Kwang OK Yoon Sun-Jung SJ Kim Jung Ryul JR Lee Sangkyu S Bae Eun Ju EJ Park Byung-Hyun BH

Cell death and differentiation 20190220 11

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 Sirt ...[more]

PMID: 30787391

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Project description:Loading-related changes in gene expression in resident cells in the tibia of female mice in the contexts of normality (WT), estrogen deficiency (WT-OVX), absence of estrogen receptor alpha (ERalpha(-/-)) and disuse due to sciatic neurectomy (WT-SN) were established by microarray. Total RNA was extracted from loaded and contra-lateral non-loaded tibiae at selected time points after a single, short period of dynamic loading sufficient to engender an osteogenic response. There were marked changes in the expression of many genes according to context as well as in response to loading within those contexts. In WT mice at 3, 8, 12 and 24 h after loading the expression of 642, 341, 171 and 24 genes, respectively, were differentially regulated compared with contra-lateral bones which were not loaded. Only a few of the genes differentially regulated by loading in the tibiae of WT mice have recognized roles in bone metabolism or have been linked previously to osteogenesis (Opn, Sost, Esr1, Tgfb1, Lrp1, Ostn, Timp, Mmp, Ctgf, Postn and Irs1, BMP and DLX5). The canonical pathways showing the greatest loading-related regulation were those involving pyruvate metabolism, mitochondrial dysfunction, calcium-induced apoptosis, glycolysis/gluconeogenesis, aryl hydrocarbon receptor and oxidative phosphorylation. In the tibiae from WT-OVX, ERalpha(-/-) and WT-SN mice, 440, 439 and 987 genes respectively were differentially regulated by context alone compared to WT. The early response to loading in tibiae of WT-OVX mice involved differential regulation compared to their contra-lateral non-loaded pair of fewer genes than in WT, more down-regulation than up-regulation and a later response. This was shared by WT-SN. In tibiae of ERalpha(-/-) mice, the number of genes differentially regulated by loading was markedly reduced at all time points. These data indicate that in resident bone cells, both basal and loading-related gene expression is substantially modified by context. Many of the genes differentially regulated by the earliest loading-related response were primarily involved in energy metabolism and were not specific to bone.

Dataset Information

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

Publications

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

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