Building Bones Back Better with NMN
When we break a bone, stem cells in our marrow choreograph a multistage process to repair and heal the fracture. These stem cells in the marrow are called bone mesenchymal stem cells (BMSCs) and are essential to bone regeneration. Delayed or failed bone fracture healing, which happens in 5-10% of cases, can often be traced back to deficient or dysfunctional BMSC activity.
Researchers from Sichuan University in China report that elevated levels of NAD+ are indispensable for BMSCs to produce bone-producing cells called osteoblasts and form bone. In mammals, NAD+ is predominantly synthesized from NMN by an enzyme called NAMPT. Li and colleagues show that blocking NAMPT stops human BMSCs from maturing into osteoblasts and reduces bone formation. On the other hand, elevating NAD+ levels by enhancing NAMPT activity increases BMSC maturation into osteoblasts and stimulates bone formation. This paradigm applies to cells in a dish and animals since blocking NAMPT in live mice inhibits bone fracture repair. Published in Stem Cell Research & Therapy, this study shows that NAD+ might provide a potential therapeutic target for bone repair and regeneration.
BMSCs are currently used as seed cells for tissue regeneration and stem cell therapy. These self-renewing cells have the potential to differentiate into many types of cells, including osteoblasts and adipocytes (fat cells). BMSCs transform into these cells in a mutually exclusive manner—that is, they typically mature into one of these two lineages. Understanding how tuning the scale to control the maturation of BMSCs to osteoblasts has a major impact on bone repair.
Multiple factors contribute to the lineage commitment of BMSCs to bone or adipogenesis, including the extracellular environment and cellular metabolism. The primary pathway for energy production in cells, oxidative phosphorylation, is one of the most critical metabolic activities in mitochondria. Cells can also generate energy in the cytoplasm through glycolysis—a less efficient way of generating energy than oxidative
phosphorylation; sugar metabolism through mitochondrial oxidative phosphorylation can generate fifteen times more energy than glycolysis. However, little is known about the roles of oxidative phosphorylation and glycolysis in regulating the cell fate decision and maturation of BMSCs.
Human bone formation is dependent on NAD+ produced by NMN
Metabolism and the role of NAD+ in teasing out the lineage determination of BMSCs. Researchers from Sichuan University have shown that cultured human bone marrow-derived mesenchymal stem cells are maturing into osteogenic cells whose metabolism shifts from glycolysis to oxidative phosphorylation. Consistent with enhanced oxidative phosphorylation, mitochondria become elongated and significantly increased in number during bone formation (osteogenesis). In contrast, BMSCs committed to maturation into adipogenic cells exhibited increased overall metabolism, increased oxidative phosphorylation and glycolytic activity.
Bone repair in mice is dependent on NAD+ produced by NMN
To evaluate the role of NAD+ in osteogenesis in mice, fracture model experiments were performed and the NAMPT inhibitor FK866 was injected. Consistent with cell culture data, the Sichuan University researchers showed that when NAMPT was inhibited, fracture healing was inhibited and cartilage and bone formation were impaired. In addition, FK866 treatment reduced the mineral density of callus—bone and cartilage materials that form connecting bridges across fractures during repair.
NMN is required for adult stem cells to generate bone. The NAMPT inhibitor FK866 blocks the formation of osteoblasts (osteoblasts (stained red)) from human BMSCs. NMN, an export of NAMPT activity, overcame the inhibitory effect of FK866 and restored the osteogenic capacity of BMSCs.
Can NAD+ boost improve bone repair?
It will be interesting to examine whether supplementation with NAD+ or its intermediates is beneficial for fracture repair. Other work on NMN and bone health and production is consistent. For example, a study published a few weeks ago showed that NMN could revive the "stemness" of MSCs by
preventing aging -- an age-related disease in which cells no longer grow or replicate. In 2020, another study revealed a potential link to NMN treatment as a treatment for osteoporosis in aging mice. This fusion of data may prompt people to venture into the therapeutic potential of NMN in human bone formation and regeneration.