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Antagonism of RANKL signaling by estrogen in osteoclasts

Award Number: R01AR082418
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: 03/22/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Antagonism of RANKL signaling by estrogen in osteoclasts - PROJECT SUMMARY/ABSTRACT Loss of estrogens at menopause is a major cause of osteoporosis due to an increase in number and activity of the cells that resorb bone called osteoclasts. Estrogens inhibit bone resorption in part via direct effects on osteoclasts. However, the cellular and molecular mechanisms responsible for the direct effects of estrogens on osteoclasts remain unclear. The work proposed in this application seeks to identify the molecular mechanisms by which estrogens directly control osteoclast number, function, or both. We found that estrogens prevent an early stimulatory effect of RANKL – the indispensable cytokine for osteoclast differentiation – on mitochondria respiration and ATP production in osteoclast progenitors. Evolutionarily Conserved Signaling Intermediate in Toll Pathway (ECSIT) is a mitochondria complex I-associated protein that regulates immune responses in macrophages in response to inflammatory signals. We found that ECSIT is essential for RANKL-induced stimulation of mitochondria activity and ATP production and a target for the anti-osteoclastogenic effects of estrogens. Estrogens also decrease NAD+ levels and NAD+/NADH ratio and promote the mitochondria pathway of apoptosis. The above observations form the foundation of the hypothesis that estrogens reduce osteoclast number and bone resorption by inhibiting RANKL stimulation of mitochondria, decreasing NAD+, and promoting mitochondria-mediated apoptosis. The work proposed will elucidate the independent contribution of ECSIT, NAD, and apoptosis to osteoclastogenesis and the effects of estrogens. We will also identify possible interactions among these pathways. To test the hypothesis, we will determine whether ECSIT stimulation of mitochondria activity is required for the bone loss caused by estrogen deficiency. This will be accomplished using mice lacking ECSIT in osteoclast lineage cells. In addition, we will examine the contribution of NAD to the estrogen deficiency-dependent increase in bone resorption using mice with loss-of- function of Nampt – an essential enzyme of the NAD salvage pathway – in osteoclast lineage cells. We will also overexpress mitochondria-targeted water-forming NADH oxidase from Lactobacillus brevis (LbNOX) in osteoclast cultures to examine the contribution of altered NAD+/NADH redox ratio to the effects of estrogen. Finally, we will investigate whether estrogens decrease osteoclast number by promoting mitochondria- mediated cell death using mice with simultaneous deletion of Bak and Bax – proteins required for mitochondria mediated apoptosis – in osteoclast lineage cells. To distinguish effects of estrogen in progenitors versus mature osteoclasts, we will examine changes in number and gene expression profiles of osteoclast lineage cells in vivo and in vitro using single cell RNA sequencing. Successful completion of this work should establish novel mechanisms that contribute to osteoclast development and its regulation by estrogens.


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 = $432,476 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/24/2026	NON-COMPETING CONTINUATION	$409,714
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/14/2026	NON-COMPETING CONTINUATION	$22,762
														Subtotal = $432,476

Issue Date FY: 2025 ( Subtotal = $409,714 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/17/2025	NON-COMPETING CONTINUATION	$409,714
														Subtotal = $409,714

Issue Date FY: 2024 ( Subtotal = $455,238 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/21/2024	NEW	$455,238
														Subtotal = $455,238

Grand Total All Awards = $1,297,428

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Antagonism of RANKL signaling by estrogen in osteoclasts

Award Number: R01AR082418

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: 03/22/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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