![]() The NAM generated in these processes can be recycled to NAD via the salvage pathway 9. The NAD-dependent sirtuins, PARPs, and cyclic ADP-ribose synthetases metabolize NAD + into NAM. The intracellular levels of NAD + are determined by the cellular redox state (i.e., NAD +/NADH) and by the balance between NAD + biosynthesis and degradation. Furthermore, plasma levels of most NAD + precursors are low and, most likely, unable to systematically sustain high NAD + production rates. For instance, the kynurenine pathway of NAD synthesis seems to occur predominantly in the liver, as several enzymes of this pathway are not expressed in most other tissues 8. The existence of different pathways leading to NAD + production raises questions regarding the relative importance of each pathway to various tissues. The Preiss–Handler and salvage pathways produce NAD from NA and NAM, respectively 7. The kynurenine pathway, also known as the de novo pathway, produces NAD from tryptophan. Vitamin B3 is a collective term for nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR) 3. NAD is synthesized from dietary precursors such as tryptophan and vitamin B3 (niacin) via several pathways 5, 6. NAD + also acts as a degradation substrate for numerous enzymes, such as sirtuins, PARPs, and cyclic ADP-ribose synthetases such as CD38 and CD157 3, 4. Conversely, the redox pair NADP +/NADPH is primarily used for anabolic processes such as lipid and cholesterol synthesis. In this role, NAD + is central for the catabolism of carbon sources in glycolysis, TCA cycle, β-oxidation, and glutaminolysis. In its oxidized state, NAD + and its phosphorylated version NADP + are able to accept two electrons, making this molecule essential for redox homeostasis. Nicotinamide adenine dinucleotide (NAD) is a critical cofactor for cellular energy metabolism and numerous cellular processes, such as cell division, DNA damage repair, and mitochondrial function 1, 2. These findings define a critical role for cell-autonomous NAD homeostasis during endochondral bone formation. ![]() In contrast, osteoblast formation still occurs in knockout mice, in line with distinctly different microenvironments and reliance on redox reactions between chondrocytes and osteoblasts. Depletion of NAD post-birth also promotes chondrocyte death, preventing further endochondral ossification and joint development. Administration of the NAD precursor nicotinamide riboside during pregnancy prevents the majority of in utero defects. At birth, Nampt ΔPrx1 exhibit dramatic limb shortening due to death of growth plate chondrocytes. Here, we generate mice with deletion of Nicotinamide Phosphoribosyltransferase ( Nampt), a critical enzyme in the NAD salvage pathway, in all mesenchymal lineage cells of the limbs. ![]() ![]() NAD levels are maintained by multiple synthetic pathways but which ones are important in bone forming cells is unknown. Systemic NAD + deficiency has been implicated in skeletal deformities during development in both humans and mice. NAD is an essential co-factor for cellular energy metabolism and multiple other processes. ![]()
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