title: Nicotinamide phosphoribosyltransferase (Nampt) affects the lineage fate determination of mesenchymal stem cells: a possible cause for reduced osteogenesis and increased adipogenesis in older individuals.
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.
authors.affiliation: Division of Orthopedics, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. Yan.Li@ki.se
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Jiaxue
authors.initials: J
authors.lastname: He
authors.forename: Björn
authors.initials: B
authors.lastname: Anderstam
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.forename: Urban
authors.initials: U
authors.lastname: Lindgren
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D016207:Cytokines / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000172:deficiency / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D003470:Culture Media; D016207:Cytokines; D009243:NAD; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1