Nicotinamide phosphoribosyltransferase (Nampt) affects the lineage fate determination of mesenchymal stem cells: A possible cause for reduced osteogenesis and increased adipogenesis in older individuals

Authors

  • Yan Li,

    Corresponding author
    1. Division of Orthopedics, Department for Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
    • Department for Clinical Science, Intervention and Technology (CLINTEC), Division of Orthopedics, Karolinska Institutet, 14186 Stockholm, Sweden.
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  • Xu He,

    1. Division of Orthopedics, Department for Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
    2. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, People's Republic of China
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  • Yulin Li,

    1. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, People's Republic of China
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  • Jiaxue He,

    1. Division of Orthopedics, Department for Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
    2. Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, People's Republic of China
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  • Björn Anderstam,

    1. Division of Renal Medicine, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
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  • Göran Andersson,

    1. Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
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  • Urban Lindgren

    1. Division of Orthopedics, Department for Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
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Abstract

Human aging is associated with a progressive decline in bone mass and an accumulation of marrow fat. We found that osteoblast differentiation was reduced and adipocyte formation increased in bone marrow stromal cells derived from aged mice compared with young controls. The increased adipogenesis correlated with a relatively lower Sirt1 activity and a lower intracellular NAD+ concentration. We suppose that these effects were caused by age-related reduction of nicotinamide phosphoribosyltransferase (Nampt), the enzyme catalyzing NAD resynthesis from nicotinamide (NAM). In support of this hypothesis, treatment with Nampt inhibitor FK866 increased adipocyte formation and reduced mineralization in primary cultured bone marrow stromal cells. In addition, knockdown of Nampt in the mouse mesenchymal cell line C3H10T1/2 cells resulted in decreased Sirt1 activity and enhanced adipogenesis. Interestingly, although Nampt deficiency resulted in both decreased intracellular NAD+ and increased NAM, the cell differentiation could be controlled only by regulation of NAM. These results indicate that the lineage fate determination of mesenchymal stem cells (MSCs) is influenced by cell energy metabolism and points to a possible mechanism for the development of senile osteoporosis. Furthermore, we suggest that side effects on bone should be considered when evaluating the long-term safety of NAD-interfering pharmaceuticals. © 2011 American Society for Bone and Mineral Research

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