# Mechanisms of decreased bone formation with aging

> **NIH NIH R56** · UNIV OF ARKANSAS FOR MED SCIS · 2022 · $455,284

## Abstract

Project Summary/Abstract
Loss of bone mass is the seminal pathology underlying the increased incidence of osteoporotic fractures in the
aged population. The cellular changes in the skeleton of aged mice are similar to those observed in aged
humans. A decrease in osteoblast number and bone formation are major contributors to skeletal aging in both
humans and mice, however the underlying mechanisms remain unclear. A reduction in the levels of coenzyme
NAD+ contributes to the functional decline of multiple tissues with age due to mitochondria dysfunction and
attenuation of the activity of NAD-dependent enzymes such as the sirtuins (SIRTs) and poly(ADP-ribose)
polymerases (PARPs). Sirt1 and Parp5 can promote the activity of the Wnt/β-catenin pathway, which is
indispensable for osteoblast formation. We have shown that osteoblast progenitor number and proliferation are
reduced in aged mice and that these changes correlate with lower levels of NAD+ and expression of nicotinamide
phosphoribosyltransferase (Nampt) – a critical enzyme in the NAD+ salvage pathway. In contrast, the levels of
the NAD+ consuming enzyme CD38 are increased with aging. Administration of the NAD precursor molecule
nicotinamide riboside (NR) to aging mice counteracts the loss of osteoblast progenitors and bone mass.
Moreover, heterozygous deletion of Nampt in cells of the mesenchymal lineage using Prx1-Cre mimics skeletal
aging. We have also obtained evidence to suggest that the deleterious effects of NAD depletion on bone mass
are mediated by mitochondrial reactive oxygen species (ROS) and the FoxO transcription factors. Notably, the
protein levels of β-catenin and stimulation of the canonical Wnt signaling in osteoblastic cells are greatly
dependent on NAD+. We hypothesize that a decline in the NAD+ salvage pathway with old age decreases
Wnt signaling and thereby osteoblast number, via FoxO-dependent and -independent mechanisms. In
Aim 1 we will elucidate the contribution of the NAD+ salvage pathway in cells of the osteoblast lineage and CD38
to skeletal homeostasis in young and old mice. To do this, we will examine the effects of Nampt deletion or
overexpression in osteoblast lineage cells, as well as the impact of CD38 in skeletal aging. In Aim 2 we will
determine the contribution of mitochondrial ROS or FoxOs in osteoprogenitors to the adverse skeletal effects of
NAD+ depletion. In Aim 3 we will investigate the effects of NAD+ on Wnt signaling by deleting Nampt and
overexpressing Wnt1. We will also examine whether the NAD+ stimulatory actions on β-catenin are dependent
on Parp5a and Parp5b. Successful completion of these studies should help us understand the mechanisms
mediating the decrease in NAD with aging and unravel how the NAD salvage pathway in osteoblast lineage cells
promotes bone formation. This work should also elucidate the interaction, or lack thereof, between ROS and
NAD+ and may suggest more targeted therapeutic approaches to slowing or preventing skeletal aging...

## Key facts

- **NIH application ID:** 10707568
- **Project number:** 2R56AR056679-11A1
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Maria Jose Almeida
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $455,284
- **Award type:** 2
- **Project period:** 2022-09-22 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707568

## Citation

> US National Institutes of Health, RePORTER application 10707568, Mechanisms of decreased bone formation with aging (2R56AR056679-11A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10707568. Licensed CC0.

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