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Mechanisms of decreased bone formation with aging

Award Number: R56AR056679
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Mechanisms of decreased bone formation with aging - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$222 )
2025	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	1/7/2025	COMPETING CONTINUATION	-$222
														Subtotal = -$222

Issue Date FY: 2022 ( Subtotal = $455,284 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	9/22/2022	COMPETING CONTINUATION	$455,284
														Subtotal = $455,284

Grand Total All Awards = $455,062

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Mechanisms of decreased bone formation with aging

Award Number: R56AR056679

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/22/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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