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

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 signa...

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Autores principales:	Ha-Neui Kim, Filipa Ponte, Aaron Warren, Rebecca Ring, Srividhya Iyer, Li Han, Maria Almeida
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/a54a3d70b3254f2d8cfecbddf28dceb2
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spelling	oai:doaj.org-article:a54a3d70b3254f2d8cfecbddf28dceb22021-12-02T14:25:21ZA decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging10.1038/s41514-021-00058-72056-3973https://doaj.org/article/a54a3d70b3254f2d8cfecbddf28dceb22021-04-01T00:00:00Zhttps://doi.org/10.1038/s41514-021-00058-7https://doaj.org/toc/2056-3973Abstract 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.Ha-Neui KimFilipa PonteAaron WarrenRebecca RingSrividhya IyerLi HanMaria AlmeidaNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 7, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Ha-Neui Kim Filipa Ponte Aaron Warren Rebecca Ring Srividhya Iyer Li Han Maria Almeida A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
description	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.
format	article
author	Ha-Neui Kim Filipa Ponte Aaron Warren Rebecca Ring Srividhya Iyer Li Han Maria Almeida
author_facet	Ha-Neui Kim Filipa Ponte Aaron Warren Rebecca Ring Srividhya Iyer Li Han Maria Almeida
author_sort	Ha-Neui Kim
title	A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
title_short	A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
title_full	A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
title_fullStr	A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
title_full_unstemmed	A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
title_sort	decrease in nad+ contributes to the loss of osteoprogenitors and bone mass with aging
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a54a3d70b3254f2d8cfecbddf28dceb2
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A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

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