title: Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation.
abstract: OBJECTIVE
  Osteogenic repair in response to bone injury is characterized by activation and differentiation of mesenchymal stem cells (MSCs) to osteoblasts. This study determined whether activation of Sirt-1 (a NAD(+)-dependent histone deacetylase) by the phytoestrogen resveratrol affects osteogenic differentiation.
  
  
  METHODS
  Monolayer and high-density cultures of MSCs and pre-osteoblastic cells were treated with an osteogenic induction medium with/without the Sirt-1 inhibitor nicotinamide or/and resveratrol in a concentration dependent manner.
  
  
  RESULTS
  MSCs and pre-osteoblastic cells differentiated to osteoblasts when exposed to osteogenic-induction medium. The osteogenic response was blocked by nicotinamide, resulting in adipogenic differentiation and expression of the adipose transcription regulator PPAR-γ (peroxisome proliferator-activated receptor). However, in nicotinamide-treated cultures, pre-treatment with resveratrol significantly enhanced osteogenesis by increasing expression of Runx2 (bone specific transcription factor) and decreasing expression of PPAR-γ. Activation of Sirt-1 by resveratrol in MSCs increased its binding to PPAR-γ and repressed PPAR-γ activity by involving its cofactor NCoR (nuclear receptor co-repressor). The modulatory effects of resveratrol on nicotinamide-induced expression of PPAR-γ and its cofactor NCoR were found to be mediated, at least in part, by Sirt-1/Runx2 association and deacetylation of Runx2. Finally, knockdown of Sirt-1 by using antisense oligonucleotides downregulated the expression of Sirt-1 protein and abolished the inhibitory effects of resveratrol, namely nicotinamide-induced Sirt-1 suppression and Runx2 acetylation, suggesting that the acetylated content of Runx2 is related to downregulated Sirt-1 expression.
  
  
  CONCLUSIONS
  These data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro. (242 words in abstract).
authors.affiliation: Institute of Anatomy, Ludwig-Maximilian-University Munich, Munich, Germany. mehdi.shakibaei@med.uni-muenchen.de
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Parviz
authors.initials: P
authors.lastname: Shayan
authors.forename: Franziska
authors.initials: F
authors.lastname: Busch
authors.forename: Constance
authors.initials: C
authors.lastname: Aldinger
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
authors.forename: Cora
authors.initials: C
authors.lastname: Lueders
authors.forename: Ali
authors.initials: A
authors.lastname: Mobasheri
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009536:Niacinamide / Q000737:chemistry / Q000494:pharmacology; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010012:Osteogenesis / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D050659:Core Binding Factor Alpha 1 Subunit; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D016376:Oligonucleotides, Antisense; D047495:PPAR gamma; D013267:Stilbenes; D009536:Niacinamide; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol