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

Aaron Warren, Ryan M. Porter, Olivia Reyes-Castro, Md Mohsin Ali, Adriana Marques-Carvalho, Ha-Neui Kim, Landon B. Gatrell, Ernestina Schipani, Intawat Nookaew, Charles A. O’Brien, Roy Morello and Maria Almeida ()
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Aaron Warren: University of Arkansas for Medical Sciences
Ryan M. Porter: University of Arkansas for Medical Sciences
Olivia Reyes-Castro: University of Arkansas for Medical Sciences
Md Mohsin Ali: University of Arkansas for Medical Sciences
Adriana Marques-Carvalho: University of Coimbra, UC-Biotech, Biocant Park
Ha-Neui Kim: University of Arkansas for Medical Sciences
Landon B. Gatrell: University of Arkansas for Medical Sciences
Ernestina Schipani: University of Pennsylvania
Intawat Nookaew: University of Arkansas for Medical Sciences
Charles A. O’Brien: University of Arkansas for Medical Sciences
Roy Morello: University of Arkansas for Medical Sciences
Maria Almeida: University of Arkansas for Medical Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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, NamptΔPrx1 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.

Date: 2023
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DOI: 10.1038/s41467-023-39392-7

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