Epigenetic regulation of Runx2 transcription and osteoblast differentiation by nicotinamide phosphoribosyltransferase

Background: Bone degenerative disorders like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Although there are studies suggesting that metabolic changes occur with stem cell differentiation, the molecular mechanisms governing energy metabolism and epigenetic modification are not understood fully. Here we reported the key role of nicotinamide phosphoribosyltransferase (Nampt), which is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide, in the osteogenic differentiation of bone marrow stromal cells. Results: Differentiated bone marrow stromal cells isolated from Nampt(+/-) mice presented with diminished osteogenesis, as evaluated by alkaline phosphatase (ALP) staining, ALP activity and osteoblast-mediated mineralization, compared to cells from Nampt(+/+) mice. Similar results were observed in differentiated Nampt-deficient C3H/10T1/2 and MC3T3-E1 cells. Further studies showed that Nampt promotes osteoblast differentiation through increased function and expression of Runx2 as tested by luciferase reporter assay, RT-PCR, and Western Blotting. Our data also demonstrated that Nampt regulates Runx2 transcription in part through epigenetic modification of H3-Lys9 acetylation. Conclusion: Our study demonstrated that Nampt plays a critical role in osteoblast differentiation through epigenetic augmentation of Runx2 transcription. NAMPT may be a potential therapeutic target of aging-related osteoporosis.