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Parathyroid hormone (PTH) modulates lipid metabolism in the skeletal niche

Award Number: R01AG069795
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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Parathyroid hormone (PTH) modulates lipid metabolism in the skeletal niche - PROJECT SUMMARY/ ABSTRACT The long-term goal of my laboratory is to develop a comprehensive understanding of how intracellular metabolic pathways impact bone health. Within this scope the current project aims to explore the osteoanabolic effects of intermittent parathyroid hormone (iPTH} via its modulation of lipid metabolism on cells within the skeletal niche. Osteoporosis and osteopenia are late-onset diseases affecting a staggering 54 million people in the U.S. In addition to the financial burden, osteoporosis-related fractures often lead to multiple comorbidities which significantly reduce longevity. While anabolic agents that increase bone formation such as PTH or PTH related protein's (PTHrP} have aided in the management of osteoporosis, patients still experience adverse side-effects. Therefore, continued development of refined therapeutic options is necessary. As such, this project presents dual, complimentary mechanisms whereby PTH signaling up-regulates lipolysis in bone marrow adipocytes {BMAdipo}, releasing lipid species into the skeletal niche, while also enhancing fatty acid oxidation in osteoblasts. Given the intimate proximity of BMAdipo to osteoblasts, it stands to reason that PTH treatment acts on both BMAdipo to liberate lipid species while also 'priming' the osteoblast to utilize these lipids as a mechanism capable of supporting the energy demanding process of bone formation. Therefore, our overarching hypothesis is that PTH's bone anabolic actions involve stimulation of lipolysis in BMAdipo and enhance fatty acid oxidation in osteoblasts. We will test this hypothesis in two specific aims. The first aim {SA 1} will determine the ability of PTH-stimulated BMAdipo lipolysis to support PTH-induced bone formation, both in vivo and in vitro. This will be accomplished using a new mouse model, developed by Co-I, designed to specifically inhibit lipolysis in BMAdipo. These mice will then be ovariectomized (OVX} or sham-operated on and be treated with PTH or vehicle control. Skeletal and metabolic parameters will be assessed at the end of the study. In addition to this experiment, lipid species released from BMAdipo upon PTH treatment will be characterized using liquid chromatography-mass spectrometry (LC-MS}. The second aim (SA2} will define PTH's ability to alter osteoblast lipid metabolism via modulation of cellular bioenergetics. Tracing of 13C1a oleic acid will be performed using LC-MS to determine fatty acid metabolic fate during PTH treatment in osteoblasts. Additionally, osteoblast mitochondrial oxidative phosphorylation substrate dependency will be measured during PTH using Seahorse XFe96 technology. Finally, osteoblast bioenergetics will be monitored using reversedphase high-performance liquid chromatography (RP-HPLC} to determine adenosine monophosphate {AMP}, adenosine diphosphate {ADP}, and ATP flux under control conditions and during PTH stimulation. In summary, the goal of this project is to enhance our understanding of PTH's ability to promote bone formation via the modulation of lipid metabolism. This project is expected to have substantial health-related influence as it will identify new areas for therapeutic exploration that are crucial to improving the management of osteoporosis.


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: 2026 ( Subtotal = -$87,500 )
2026	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	001	5	2/11/2026	SUPPLEMENT FOR EXPANSION	$0
2026	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	5	2/11/2026	NON-COMPETING CONTINUATION	-$87,500
														Subtotal = -$87,500

Issue Date FY: 2025 ( Subtotal = $122,500 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	5	5/16/2025	SUPPLEMENT FOR EXPANSION	$122,500
														Subtotal = $122,500

Issue Date FY: 2024 ( Subtotal = $421,363 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	5	5/7/2024	NON-COMPETING CONTINUATION	$421,363
														Subtotal = $421,363

Issue Date FY: 2023 ( Subtotal = $421,534 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	4	6/12/2023	NON-COMPETING CONTINUATION	$421,534
														Subtotal = $421,534

Issue Date FY: 2022 ( Subtotal = $421,701 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	3	8/5/2022	NON-COMPETING CONTINUATION	$421,701
														Subtotal = $421,701

Issue Date FY: 2021 ( Subtotal = $421,863 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	2	6/25/2021	NON-COMPETING CONTINUATION	$421,863
														Subtotal = $421,863

Issue Date FY: 2020 ( Subtotal = $440,270 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	1	9/16/2020	NEW	$440,270
														Subtotal = $440,270

Grand Total All Awards = $2,161,731

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Parathyroid hormone (PTH) modulates lipid metabolism in the skeletal niche

Award Number: R01AG069795

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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