ArticleCell death and differentiation2019
Sirtuin 6 in preosteoclasts suppresses age- and estrogen deficiency-related bone loss by stabilizing estrogen receptor α.
Article in Cell death and differentiation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 73 citations in OpenAlex.
- SIRT6 Mediates Sterol-Dependent Feedback Regulation of Cholesterol Biosynthetic Genes in Hepatocytes.Biomolecules & therapeutics · 2026Article
- ERα/SIRT1 signaling mediates the metabolic regulatory benefits of pterostilbene.The Journal of biological chemistry · 2026Article
- Hepatic SIRT6 Deficiency Accelerates Female-Specific Aging Through SULT1E1-Mediated Estrogen Depletion.International journal of molecular sciences · 2026Article
- Review
- Sirt3 Genetically Engineered Apoptotic Bodies Alleviate Skeletal Aging by Limiting Aggravated NLRP3 Inflammasome Activation of Senescent Macrophages.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- HSD17B7 Counters Bone Loss in Estrogen Deficiency via Estrogen Receptor Stabilization and Mediates the Effect of Raloxifene.MedComm · 2026Article
- The triangular drivers of bone aging: mechanistic insights and therapeutic targets in cellular senescence, estrogen deficiency, and gut microenvironment dysregulation.Frontiers in cell and developmental biology · 2026Review
- Sirtuins in Women's Health.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Addressing osteoblast senescence: Molecular pathways and the frontier of anti-ageing treatments.Clinical and translational medicine · 2025Review
- New Perspectives on Postmenopausal Osteoporosis: Mechanisms and Potential Therapeutic Strategies of Sirtuins and Oxidative Stress.Antioxidants (Basel, Switzerland) · 2025Review
- The SIRT6 Activator MDL-800 Inhibits PPARα and Fatty acid Oxidation-Related Gene Expression in Hepatocytes.Biomolecules & therapeutics · 2025Article
- Review
- Role of sirtuins in obesity and osteoporosis: molecular mechanisms and therapeutic targets.Cell communication and signaling : CCS · 2025Review
- Exercise ameliorates osteopenia in mice via intestinal microbial-mediated bile acid metabolism pathway.Theranostics · 2025Article
- Research advances on silence information regulator 6 as a potential therapeutic target for bone regeneration and repair.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2024Review
- Exploration of the miR-187-3p/CNR2 pathway in modulating osteoblast differentiation and treating postmenopausal osteoporosis through mechanical stress.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Angelicin improves osteoporosis in ovariectomized rats by reducing ROS production in osteoclasts through regulation of the KAT6A/Nrf2 signalling pathway.Chinese medicine · 2024Article
- Osteoclasts and osteoarthritis: Novel intervention targets and therapeutic potentials during aging.Aging cell · 2024Review
- Combined Effects of Polystyrene Nanosphere and Homosolate Exposures on Estrogenic End Points in MCF-7 Cells and Zebrafish.Environmental health perspectives · 2024Article
- Synthesis, andCurrent computer-aided drug design · 2024Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 results suggest that deacetylation and upregulation of ERα 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.
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