title: The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.
abstract: Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of action was a source of controversy. We studied the effect of SRT2183 and SRT3025 on osteoclastogenesis in bone-marrow derived macrophages (BMMs) in vitro, and discovered that these STACs inhibit RANKL-induced osteoclast differentiation, fusion and resorptive capacity without affecting osteoclast survival. SRT2183 and SRT3025 activated AMPK, increased Sirt1 expression and decreased RelA/p65 lysine310 acetylation, critical for NF-κB activation, and an established Sirt1 target. However, inhibition of osteoclastogenesis by these STACs was also observed in BMMs derived from sirt1 knock out (sirt1-/-) mice lacking the Sirt1 protein, in which neither AMPK nor RelA/p65 lysine 310 acetylation was affected, confirming that these effects require Sirt1, but suggesting that Sirt1 is not essential for inhibition of osteoclastogenesis by these STACs under these conditions. In sirt1 null osteoclasts treated with SRT2183 or SRT3025 Sirt3 was found to be down-regulated. Our findings suggest that SRT2183 and SRT3025 activate Sirt1 and inhibit RANKL-induced osteoclastogenesis in vitro however under conditions of Sirt1 deficiency can affect Sirt3. As aging is associated with reduced Sirt1 level and activity, the influence of STACs on Sirt3 needs to be investigated in vivo in animal and human disease models of aging and osteoporosis.
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Gurt
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Artsi
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Cohen-Kfir
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Hamdani
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Ben-Shalom
authors.affiliation: The Einstein Institute of Mathematics; The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Feinstein
authors.affiliation: Department of Orthopedics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Madi
authors.initials: M
authors.lastname: El-Haj
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Dresner-Pollak
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000502:physiology*; D056564:Sirtuin 1 / Q000502:physiology*; D056566:Sirtuin 3 / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000813:Anilides; D006576:Heterocyclic Compounds, 4 or More Rings; D053245:RANK Ligand; C525423:SRT2183; C000601293:SRT3025; C525046:Sirt3 protein, mouse; D013844:Thiazoles; C505689:Tnfsf11 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D056566:Sirtuin 3