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Osteocyte Control of Bone Remodeling

Award Number: R01AR049794
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: 09/29/2003
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Osteocyte Control of Bone Remodeling - Abstract Osteoclast formation depends on the cytokine receptor activator of NFB ligand (RANKL), whose actions are inhibited by the decoy receptor osteoprotegerin (OPG). Osteocytes are an important source of RANKL and we have recently shown that osteoblasts, but not osteocytes, are an essential source of the OPG that suppresses resorption of cancellous bone. In contrast, osteoblasts and osteocytes provide only a portion of the OPG protecting cortical bone. Thus, the identity of the cells providing the OPG that protects large regions of cortical bone remains unclear, but may involve osteoblast progenitors and vascular endothelial cells, both of which express OPG. Previous studies suggest that a major function of beta-catenin is to promote OPG expression in osteocytes. Our finding that osteoblasts, but not osteocytes, are a major source of OPG necessitates a reevaluation of the role of beta-catenin in osteocytes. Previous beta-catenin loss-of-function studies have been hampered by the lack of Cre driver strains that can distinguish between osteoblasts and osteocytes and by the dramatic bone loss caused by beta-catenin deletion in late-stage osteoblastic cells. That osteoblasts are an important source of OPG also suggests that the rapid increase in resorption and rebound bone loss following discontinuation of anti-RANKL (denosumab) therapy may be due, in part, to the absence of osteoblasts, and thus OPG, during the period following discontinuation. Based on these findings, we propose the hypotheses that osteoblast progenitors or vascular endothelial cells are important sources of the OPG protecting cortical bone and that the beta-catenin pathway in osteocytes contributes to bone remodeling independent of its control of OPG expression. We also propose that the lack of osteoblasts, and thus OPG, contributes to the rebound resorption following discontinuation of denosumab. Aim 1 will identify cellular sources of OPG that control cortical bone resorption by deleting a conditional OPG allele in mesenchymal progenitors using Prx1-Cre mice, and vascular endothelial cells using Tek-Cre mice, and compare the effects on cortical bone to those seen in OPG- null mice. Aim 2 will determine the role of beta-catenin in osteocytes by deletion of beta-catenin using Sost-Cre mice, which delete target genes in osteocytes but not osteoblasts. Aim 3 will determine whether the rebound resorption caused by discontinuation of denosumab results in part from the profound lack of osteoblasts producing OPG using a novel humanized RANKL mouse line treated with denosumab. These mice will be used to map the cellular and molecular conditions associated with discontinuation of denosumab and to determine whether promotion of osteoblast formation via anti-sclerostin antibody administration can restore OPG levels and ameliorate rebound resorption.


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 = $300,960 )
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	19	3/12/2025	NON-COMPETING CONTINUATION	$300,960
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	19	5/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $300,960

Issue Date FY: 2024 ( Subtotal = $324,368 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	18	6/12/2024	NON-COMPETING CONTINUATION	$23,408
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	18	3/19/2024	NON-COMPETING CONTINUATION	$300,960
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	5/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $324,368

Issue Date FY: 2023 ( Subtotal = $334,400 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	4/21/2023	NON-COMPETING CONTINUATION	$334,400
														Subtotal = $334,400

Issue Date FY: 2022 ( Subtotal = $334,400 )
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	16	3/11/2022	COMPETING CONTINUATION	$334,400
														Subtotal = $334,400

Issue Date FY: 2021 ( Subtotal = -$6,184 )
2021	2019	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	15	8/26/2021	NON-COMPETING CONTINUATION	-$6,184
														Subtotal = -$6,184

Issue Date FY: 2019 ( Subtotal = $327,800 )
2019	2019	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	15	3/27/2019	NON-COMPETING CONTINUATION	$327,800
														Subtotal = $327,800

Issue Date FY: 2018 ( Subtotal = $378,793 )
2018	2018	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	14	4/14/2018	NON-COMPETING CONTINUATION	$378,793
														Subtotal = $378,793

Issue Date FY: 2017 ( Subtotal = $378,793 )
2017	2017	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	13	3/21/2017	NON-COMPETING CONTINUATION	$340,914
2017	2017	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	001	13	6/15/2017	NON-COMPETING CONTINUATION	$37,879
														Subtotal = $378,793

Issue Date FY: 2016 ( Subtotal = $360,029 )
2016	2016	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	12	9/2/2016	SUPPLEMENT FOR EXPANSION	$32,229
2016	2016	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	3/3/2016	NON-COMPETING CONTINUATION	$327,800
														Subtotal = $360,029

Issue Date FY: 2015 ( Subtotal = $327,800 )
2015	2015	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	3/10/2015	COMPETING CONTINUATION	$327,800
														Subtotal = $327,800

Issue Date FY: 2012 ( Subtotal = $303,178 )
2012	2012	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/12/2012	NON-COMPETING CONTINUATION	$303,178
														Subtotal = $303,178

Issue Date FY: 2011 ( Subtotal = $303,178 )
2011	2011	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/16/2011	NON-COMPETING CONTINUATION	$303,178
														Subtotal = $303,178

Issue Date FY: 2010 ( Subtotal = $315,810 )
2010	2010	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	6/14/2010	NON-COMPETING CONTINUATION	$315,810
														Subtotal = $315,810

Issue Date FY: 2009 ( Subtotal = $319,000 )
2009	2009	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	6/18/2009	NON-COMPETING CONTINUATION	$319,000
														Subtotal = $319,000

Issue Date FY: 2008 ( Subtotal = $316,228 )
2008	2008	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/21/2008	COMPETING CONTINUATION	$316,228
														Subtotal = $316,228

Issue Date FY: 2007 ( Subtotal = $241,010 )
2007	2007	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/15/2007	NON-COMPETING CONTINUATION	$241,010
														Subtotal = $241,010

Issue Date FY: 2006 ( Subtotal = $248,207 )
2006	2006	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/30/2006	NON-COMPETING CONTINUATION	$248,207
														Subtotal = $248,207

Issue Date FY: 2005 ( Subtotal = $275,480 )
2005	2005	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/27/2005	NON-COMPETING CONTINUATION	$275,480
														Subtotal = $275,480

Issue Date FY: 2004 ( Subtotal = $275,480 )
2004	2004	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/30/2004	NON-COMPETING CONTINUATION	$275,480
														Subtotal = $275,480

Issue Date FY: 2003 ( Subtotal = $275,480 )
2003	2003	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST, M S 545	LITTLE ROCK	AR	72205	PULASKI	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/29/2003	NEW	$275,480
														Subtotal = $275,480

Grand Total All Awards = $5,934,210

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Osteocyte Control of Bone Remodeling

Award Number: R01AR049794

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: 09/29/2003

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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