title: Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling.
abstract: Sirtuin 6 (Sirt6) is a mammalian homologue of NAD⁺-dependent histone deacetylase Sir2. Although Sirt6⁻/⁻ mice exhibit growth retardation, the role of Sirt6 in cartilage metabolism is unclear. The aim of this study was to investigate the Sirt6 signaling pathway in cartilage metabolism. Immunohistological evaluation of the tibial growth plate in Sirt6⁻/⁻ mice exhibited impaired proliferation and differentiation of chondrocytes, reduced expression of Indian hedgehog (Ihh), and a senescent phenotype. When Sirt6 was knocked down in chondrocytes in vitro, expression of Ihh and its downstream genes were reduced. Impaired differentiation by Sirt6 silencing was completely rescued by administration of a Hh signal agonist. When sirtuins were activated, chondrocyte differentiation was enhanced together with activation of Ihh signal, and these effects were abrogated by Sirt6 silencing. ChIP assay revealed the affinity of ATF4 to the Ihh promoter was markedly decreased by Sirt6 knockdown. These data indicate Sirt6 directly controls proliferation and differentiation of chondrocytes.
authors.affiliation: Department of Rehabilitation Medicine, Graduate School, Tokyo Medical and Dental University 1-5-45 Yushima Bunkyo-ku Tokyo Japan, 113-8519.
authors.forename: Jinying
authors.initials: J
authors.lastname: Piao
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tsuji
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ochi
authors.forename: Munetaka
authors.initials: M
authors.lastname: Iwata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koga
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.forename: Sadao
authors.initials: S
authors.lastname: Morita
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asou
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics; D005786:Gene Expression Regulation; D005838:Genotype; D006132:Growth Plate / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C514061:ihh protein, mouse; D051701:Activating Transcription Factor 4; C501860:Sirt6 protein, mouse; D037761:Sirtuins