Journal Article

The NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice

Kim, Ha-Neui, Schipani, Ernestina, Porter, Ryan M., Reyes-Castro, Olivia, Almeida, Maria, Warren, Aaron, O’Brien, Charles A., Gatrell, Landon B., Nookaew, Intawat, Ali, Md Mohsin, Morello, Roy, Marques-Carvalho, Adriana

2023

Overview

NAD is an essential co-factor for cellular energy metabolism and multiple other processes. Systemic NAD + deficiency has been implicated in skeletal deformities during development in both humans and mice. NAD levels are maintained by multiple synthetic pathways but which ones are important in bone forming cells is unknown. 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. At birth, Nampt ΔPrx1 exhibit dramatic limb shortening due to death of growth plate chondrocytes. Administration of the NAD precursor nicotinamide riboside during pregnancy prevents the majority of in utero defects. Depletion of NAD post-birth also promotes chondrocyte death, preventing further endochondral ossification and joint development. In contrast, osteoblast formation still occurs in knockout mice, in line with distinctly different microenvironments and reliance on redox reactions between chondrocytes and osteoblasts. These findings define a critical role for cell-autonomous NAD homeostasis during endochondral bone formation. Deficiency in NAD+ has been implicated in skeletal deformities during development in both humans and mice. Here, the authors use mice that lack the critical enzyme of the NAD+ salvage pathway Nampt in mesenchymal lineage cells to show that the NAD salvage pathway is indispensable for endochondral but not intramembranous bone development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/51 / 14/32 / 38/39 / 38/77 / 38/88 / 631/136/818 / 631/136/819 / 631/337/572 / 631/80/304 / 64/110 / Animals / Bone growth / Chondrocytes / Cytokines - metabolism / Death / Endochondral bone / Energy Metabolism / Enzymes / Growth plate / Homeostasis / Humanities and Social Sciences / Humans / Intramembraneous bone / Mesenchyme / Mice / Mice, Knockout / Microenvironments / multidisciplinary / NAD / NAD - metabolism / Nicotinamide / Nicotinamide phosphoribosyltransferase / Ossification / Osteoblasts / Osteogenesis / Oxidation-Reduction / Phosphoribosyltransferase / Redox reactions / Science / Science (multidisciplinary)