A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

Ha-Neui Kim,Li Han,Filipa Ponte,Aaron Warren,Srividhya Iyer,Maria Almeida,Rebecca Ring

doi:10.1038/s41514-021-00058-7

Abstract

Age-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence. The forkhead box O (FoxO) transcription factors attenuate Wnt/β-catenin signaling and the proliferation of osteoprogenitors, thereby decreasing bone formation. The NAD+-dependent Sirtuin1 (Sirt1) deacetylates FoxOs and β-catenin in osteoblast progenitors and, thereby, increases bone mass. However, it remains unknown whether the Sirt1/FoxO/β-catenin pathway is dysregulated with age in osteoblast progenitors. We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution.

Highlights

Loss of bone mass is a major cause for the occurrence of osteoporotic fractures in the aged population[1,2,3]
We first examined the status of forkhead box O (FoxO) acetylation and levels of Sirt[1] in bone marrow-derived osteoprogenitor cell cultures from 6- and
Using mice in which osteoprogenitor cells expressing Osx1-Cre are labeled with a red fluorescent protein (Osx1-Cre;TdRFP mice), we have previously shown that the number of Osx1-TdRFP+ cells greatly declines with aging, and that bone marrow stromal cells from old mice form fewer mineralized nodules when cultured under osteogenic conditions[13]

Summary

Introduction

Loss of bone mass is a major cause for the occurrence of osteoporotic fractures in the aged population[1,2,3]. It is well documented that trabecular bone mass and cortical thickness decrease and intracortical porosity increases with age, with particular incidence in women[4,5,6]. With aging the number of osteoblasts slowly declines leading to unbalanced remodeling and loss of bone mass[8]. Mice lose trabecular and cortical bone mass with age due to unbalanced remodeling and develop cortical porosity[9,10,11,12]. The decrease in bone formation with age is associated with lower osteoprogenitor numbers[13]; the cellular and molecular mechanisms responsible for skeletal aging remain unclear

Methods

Results

Conclusion