Abstract
ObjectiveOsteogenic 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.MethodsMonolayer 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.ResultsMSCs 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.ConclusionThese data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro. (242 words in abstract)
Highlights
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into distinct connective tissue cell types [1,2]
These data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro. (242 words in abstract)
To test whether activation of Sirt-1 inhibits adipogenesis during osteoblastic differentiation [19,39], MSC cultures were treated with resveratrol and co-treated with various concentrations of nicotinamide in osteogenic induction medium
Summary
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into distinct connective tissue cell types (i.e. osteoblasts, chondroblasts, adipocytes, myoblasts, etc.) [1,2]. Bone marrow is a good source for MSCs, the cells are available in limited quantities [2]. An alternative source for MSCs is adipose tissue; adipose derived MSCs can differentiate down the adipogenic, chondrogenic, myogenic, neurogenic, and osteogenic cell lineage pathways [3]. Hormone replacement therapy (HRT) inhibits endocrine-deficient postmenopausal osteoporosis and can reduce the incidence of bone fractures [6], but adverse side effects of these drugs have recently come to light. HRT increases the risk of developing breast and endometrial cancer [7] and has other undesirable side effects including fluid retention, headaches, mood swings and depression, which can significantly reduce quality of life in women. Safer, natural and more selective pharmacotherapies and natural remedies for menopause-induced osteoporosis are needed
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