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Studies of the fate of the osteoclast

Award Number: R01AR043510
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Studies of the fate of the osteoclast - Project Summary/Abstract Osteoporosis is a common disease of aging, caused by a combination of increased osteoclastic (OC) bone resorption and decreased osteoblastic (OB) bone formation. Low-level chronic inflammation (LLCI), characterized by increased levels of pro-inflammatory factors induced by activated NF-κB signaling, contributes to the pathogenesis of age-related osteoporosis by stimulating OC and/or inhibiting OB differentiation. However, the molecular mechanisms by which LLCI induces bone loss remain incompletely understood. Our recently published findings indicate that protein levels of TNF receptor associated factor 3 (TRAF3), which negatively regulates NF-κB signaling, are reduced in the bone marrow (BM) of aged mice. This is because increased amounts of TGFβ released from resorbing bone during aging induce ubiquintin- mediated degradation of TRAF3 by mesenchymal stromal cells (MSCs). This reduction in TRAF3 levels in MSCs leads to increased production of the chemokine, SDF1, and subsequent accumulation of a novel subset of B cell cells (CD19+, B220+ and IgM+) expressing RANKL and CXCR4 (an SDF1 receptor) that we have identified in the BM during aging. We have called this subset of RANKL+CXCR4+ B cells as RCBs for short. RCBs directly induce OC formation and produce a soluble factor(s) that inhibits OB differentiation. Importantly, either plerixafor, a FDA-approved CXCR4 inhibitor, or SM164, an inhibitor of IAP proteins, which prevents TGFβ1-induced TRAF3 degradation in MSCs, increased trabecular bone mass, associated with reduced accumulation of RCBs in the BM of aged mice. Our proposed studies will 1) fully characterize RCBs phenotypically, determine if they are present in humans and if CXCR4 in B cells mediates their accumulation in the BM of aging mice; 2) determine if TRAF3 expressed by MSCs regulates the accumulation of RCBs in BM by modulating SDF1 expression; and 3) determine if plerixafor prevents age-related osteoporosis by depleting RCBs from BM and if targeting it to bone increases its efficacy and reduces adverse effects for the prevention of age-related osteoporosis. Completion of the proposed studies will determine the mechanisms whereby this novel set of B cells contributes to bone loss by stimulating bone resorption and inhibiting bone formation during age-related osteoporosis and importantly, will provide proof of principle that plerixafor or a bone- targeted formulation of it may be a novel treatment for age-related 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: 2025 ( Subtotal = $465,385 )
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	28	1/16/2025	NON-COMPETING CONTINUATION	$465,385
														Subtotal = $465,385

Issue Date FY: 2024 ( Subtotal = $501,582 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	27	12/22/2023	NON-COMPETING CONTINUATION	$465,385
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	27	6/14/2024	NON-COMPETING CONTINUATION	$36,197
														Subtotal = $501,582

Issue Date FY: 2023 ( Subtotal = $525,565 )
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	26	1/4/2023	NON-COMPETING CONTINUATION	$473,008
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	26	2/22/2023	NON-COMPETING CONTINUATION	$52,557
														Subtotal = $525,565

Issue Date FY: 2022 ( Subtotal = $554,809 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	25	5/25/2022	NON-COMPETING CONTINUATION	$50,438
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	3/15/2022	NON-COMPETING CONTINUATION	$504,371
														Subtotal = $554,809

Issue Date FY: 2021 ( Subtotal = $571,531 )
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	24	2/1/2021	COMPETING CONTINUATION	$571,531
2021	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	23	5/25/2021	NON-COMPETING CONTINUATION	$0
2021	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	1/22/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $571,531

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	7/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $337,700 )
2018	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	7/27/2018	NON-COMPETING CONTINUATION	$337,700
														Subtotal = $337,700

Issue Date FY: 2017 ( Subtotal = $337,700 )
2017	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	22	7/11/2017	NON-COMPETING CONTINUATION	$337,700
														Subtotal = $337,700

Issue Date FY: 2016 ( Subtotal = $337,700 )
2016	2016	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	21	6/30/2016	NON-COMPETING CONTINUATION	$337,700
														Subtotal = $337,700

Issue Date FY: 2015 ( Subtotal = $337,700 )
2015	2015	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	7/7/2015	NON-COMPETING CONTINUATION	$337,700
														Subtotal = $337,700

Issue Date FY: 2014 ( Subtotal = $337,700 )
2014	2014	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	19	8/12/2014	COMPETING CONTINUATION	$337,700
2014	2013	UNIVERSITY OF ROCHESTER	910 GENESEE STREET SUITE 200	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	8/8/2014	NON-COMPETING CONTINUATION	$0
2014	2013	UNIVERSITY OF ROCHESTER	910 GENESEE STREET SUITE 200	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	8/7/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,700

Issue Date FY: 2013 ( Subtotal = $313,864 )
2013	2013	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	7/26/2013	NON-COMPETING CONTINUATION	$16,519
2013	2013	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	1/25/2013	NON-COMPETING CONTINUATION	$297,345
														Subtotal = $313,864

Issue Date FY: 2012 ( Subtotal = $330,383 )
2012	2012	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	2/26/2012	NON-COMPETING CONTINUATION	$330,383
														Subtotal = $330,383

Issue Date FY: 2011 ( Subtotal = $329,046 )
2011	2011	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	16	7/27/2011	NON-COMPETING CONTINUATION	$20,565
2011	2011	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	1/26/2011	NON-COMPETING CONTINUATION	$308,481
														Subtotal = $329,046

Issue Date FY: 2010 ( Subtotal = $341,736 )
2010	2010	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	1/27/2010	NON-COMPETING CONTINUATION	$341,736
														Subtotal = $341,736

Issue Date FY: 2009 ( Subtotal = $344,070 )
2009	2009	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	14	2/13/2009	COMPETING CONTINUATION	$336,424
2009	2009	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	14	3/31/2009	COMPETING CONTINUATION	$7,646
2009	2008	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	2/13/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $344,070

Issue Date FY: 2008 ( Subtotal = $289,776 )
2008	2008	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	2/6/2008	NON-COMPETING CONTINUATION	$289,776
														Subtotal = $289,776

Issue Date FY: 2007 ( Subtotal = $295,691 )
2007	2007	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	3/5/2007	NON-COMPETING CONTINUATION	$295,691
														Subtotal = $295,691

Issue Date FY: 2006 ( Subtotal = $304,522 )
2006	2006	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	2/27/2006	NON-COMPETING CONTINUATION	$304,522
														Subtotal = $304,522

Issue Date FY: 2005 ( Subtotal = $311,850 ) (Continued on the next page)
Grand Total All Awards = $8,871,701

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Studies of the fate of the osteoclast

Award Number: R01AR043510

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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