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
References
Dec 16, 1998·Osteoporosis International : a Journal Established As Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA·A C LookerR Lindsay
Mar 30, 2001·The Journal of Biological Chemistry·C WangR G Pestell
Dec 24, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Gil MorFortune Kohen
Apr 2, 2003·Molecular Cell·George ReidFrank Gannon
Dec 18, 2004·Cancer Research·Yukun CuiSuzanne A W Fuqua
Jun 18, 2005·Molecular Endocrinology·Stephanie SentisLaura Corbo
Feb 25, 2006·Molecular Endocrinology·Mi Young KimW Lee Kraus
Jul 12, 2007·The Journal of Biological Chemistry·Maria AlmeidaStavros C Manolagas
Sep 7, 2007·Cell·Takashi NakamuraShigeaki Kato
Jan 26, 2008·The EMBO Journal·Susan A KrumMyles Brown
Apr 5, 2008·Molecular Endocrinology·Nicholas B BerryKenneth P Nephew
Jul 5, 2008·Cell Metabolism·Kevin J PearsonRafael de Cabo
Jan 13, 2009·Cell·Tiara L A KawaharaKatrin F Chua
Jan 7, 2010·Endocrine Reviews·Stavros C Manolagas
Jan 8, 2010·Molecular Endocrinology·Marta Martin-MillanStavros C Manolagas
Apr 15, 2010·Breast Cancer Research : BCR·Sung-Hye KimMi-Ock Lee
Mar 27, 2012·Molecular Endocrinology·Piergiorgio La RosaFilippo Acconcia
Aug 7, 2012·Cell·Li QiangDomenico Accili
Sep 18, 2013·Nature Reviews. Endocrinology·Stavros C ManolagasMaria Almeida
Feb 6, 2014·PloS One·Young-Sool HahSang-Il Lee
May 3, 2014·Trends in Cell Biology·Shin-ichiro Imai, Leonard Guarente
Jun 21, 2014·Endocrinology·Hanna ArtsiRivka Dresner-Pollak
Aug 27, 2016·Clinical Breast Cancer·Angeles C Tecalco-Cruz, Josué O Ramírez-Jarquín
Nov 4, 2016·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Serra UcerStavros C Manolagas
Jun 14, 2017·Diabetes·Youngyi LeeByung-Hyun Park
Sep 25, 2017·PloS One·Kayvan ZainabadiLeonard Guarente
Feb 7, 2018·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Stavros C Manolagas
Citations
Oct 9, 2019·Cells·Chun Wang, Gabriel Mbalaviele
Sep 22, 2019·Experimental & Molecular Medicine·In Hyuk BangByung-Hyun Park
Nov 13, 2019·Aging·Lin LiSihua Gao
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
Jan 5, 2021·Aging Cell·Qiangqiang LiWayne Yuk-Wai Lee
Nov 7, 2020·Melanoma Research·Blair N HolmanKasey L Couts
Mar 27, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chiaki YamadaAlexandru Movila
Jun 5, 2021·Nature Communications·Fujun JinXiaogang Wang
Jun 15, 2021·Aging Cell·In Hyuk BangEun Ju Bae
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