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      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Resveratrol Mediated Modulation of Sirt-1/Runx2 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells: Potential Role of Runx2 Deacetylation

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          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.

          Conclusion

          These data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro. ( 242 words in abstract)

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          Most cited references41

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          Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction.

          Marcia Haigis, Leonard Guarente (2006)
          Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, worms and flies. Mammals contain seven homologs of yeast Sir2, SIRT1-7. Here, we review recent findings demonstrating the role of these mammalian sirtuins as regulators of physiology, calorie restriction, and aging. The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging.
          Article 0 comments Cited 340 times – based on 0 reviews     Review now
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            Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain.

            W Gu, R G Roeder (1997)
            The tumor suppressor p53 exerts antiproliferation effects through its ability to function as a sequence-specific DNA-binding transcription factor. Here, we demonstrate that p53 can be modified by acetylation both in vivo and in vitro. Remarkably, the site of p53 that is acetylated by its coactivator, p300, resides in a C-terminal domain known to be critical for the regulation of p53 DNA binding. Furthermore, the acetylation of p53 can dramatically stimulate its sequence-specific DNA-binding activity, possibly as a result of an acetylation-induced conformational change. These observations clearly indicate a novel pathway for p53 activation and, importantly, provide an example of an acetylation-mediated change in the function of a nonhistone regulatory protein. These results have significant implications regarding the molecular mechanisms of various acetyltransferase-containing transcriptional coactivators whose primary targets have been presumed to be histones.
            Article 0 comments Cited 325 times – based on 0 reviews     Review now
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              Duration of nuclear NF-kappaB action regulated by reversible acetylation.

              Chen Lf, W Fischle, E Verdin … (2001)
              The nuclear expression and action of the nuclear factor kappa B (NF-kappaB) transcription factor requires signal-coupled phosphorylation and degradation of the IkappaB inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm. The subsequent molecular events that regulate the termination of nuclear NF-kappaB action remain poorly defined, although the activation of de novo IkappaBalpha gene expression by NF-kappaB likely plays a key role. Our studies now demonstrate that the RelA subunit of NF-kappaB is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with IkappaBalpha. Acetylated RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction promotes effective binding to IkappaBalpha and leads in turn to IkappaBalpha-dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch that both controls the duration of the NF-kappaB transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-kappaB-IkappaBalpha complexes.
              Article 0 comments Cited 269 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 23 April 2012
                Volume: 7
                Issue: 4
                Electronic Location Identifier: e35712
                Affiliations
                [1 ]Institute of Anatomy, Ludwig-Maximilian-University Munich, Munich, Germany
                [2 ]Investigating Institute Molecular Biological System Transfer, Tehran, Iran
                [3 ]Department of Thoracic and Cardiovascular Surgery, Laboratory for Tissue Engineering, German Heart Institute Berlin, Berlin, Germany
                [4 ]Division of Veterinary Medicine, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, United Kingdom
                Institut de Génomique Fonctionnelle de Lyon, France
                Author notes

                Conceived and designed the experiments: MS PS AM. Performed the experiments: FB CA CL CB. Analyzed the data: PS AM MS. Contributed reagents/materials/analysis tools: AM PS MS. Wrote the paper: MS AM FB.

                Article
                Publisher ID: PONE-D-12-00832
                DOI: 10.1371/journal.pone.0035712
                PMC ID: 3335081
                PubMed ID: 22539994
                SO-VID: 587efe39-41e4-47d1-a66c-40e70c3f592e
                Copyright © Shakibaei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 10 January 2012
                Date accepted : 20 March 2012
                Page count
                Pages: 13
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Developmental Biology
                Subject: Stem Cells
                Subject: Mesenchymal Stem Cells
                Subject: Molecular Cell Biology
                Subject: Gene Expression
                Subject: Histone Modification
                Subject: Medicine
                Subject: Anatomy and Physiology
                Subject: Musculoskeletal System
                Subject: Bone
                Subject: Complementary and Alternative Medicine
                Subject: Nutrition
                Subject: Women's Health
                Subject: Osteopenia and Osteoporosis

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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