Friday, May 9, 2025 5/9/2025

Response of the Osteoporotic Skeleton to Mechanical Loading

Award Number: R01AR047867
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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Response of the Osteoporotic Skeleton to Mechanical Loading - PROJECT SUMMARY Wnt signaling and mechanical loading are key regulators of skeletal health. Wnt signaling initiates when a Wnt ligand binds to frizzled (FZD) and LRP5/6 co-receptors. Several Wnt pathway factors (Lrp5, Sost) have known roles in bone’s anabolic response to loading. In the past funding period, we focused on the Wnt ligands (‘Wnts’), which have been relatively understudied. We discovered that Wnt ligand secretion by Osx+ bone cells (osteoblasts/osteocytes) is essential for the anabolic response to skeletal loading, and that Wnt1 upregulation in particular is required. But with aging, loading induces less Wnt1 upregulation and less bone formation. We now shift focus to intervention, and to test the overall hypothesis that molecules that mimic Wnts can rescue the loss of bone mass and mechanoresponsiveness that are hallmarks of aging. The ability to test this hypothesis is enabled by the recent development of Wnt surrogates – antibody-based molecules that function like Wnt ligands by directly binding FZD and LRP5/6. In contrast to sclerostin antibody-based treatments that work by “inhibiting the inhibitor”, Wnt surrogates directly activate Wnt signaling. Our pilot data show that a novel tetravalent molecule that targets several FZD receptors and LRP5 potently increases bone formation, bone mass and strength in young-adult mice. We propose to test whether this LRP5-binding Wnt surrogate is effective in increasing bone mass in two mouse models of osteoporosis – aging and Wnt1 conditional deletion (which models the early-onset osteoporosis that afflicts people with WNT1 mutations). We also will evaluate the possible synergy between Wnt surrogate treatment and mechanical loading, and test whether the surrogate rescues the impaired response to loading seen in aged mice and in Wnt1 mutant mice. Next, because LRP5 and LRP6 are each required for skeletal health, we will take advantage of the modularity of the Wnt surrogate platform to compare cell and bone responses to LRP5-binding and LRP6-binding surrogates. Finally, we will test whether the LRP6-binding surrogate can rescue osteoporosis in mice with conditional deletion of Lrp5, which models human osteoporosis-pseudoglioma (OPPG) syndrome. Development of Wnt surrogates addresses a need for new, targeted anabolic therapies that can be used for a personalized approach to the treatment 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: 2025 ( Subtotal = $504,225 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	21	4/4/2025	NON-COMPETING CONTINUATION	$504,225
2025	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	1/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $504,225

Issue Date FY: 2024 ( Subtotal = $543,441 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	20	6/12/2024	NON-COMPETING CONTINUATION	$39,216
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	4/24/2024	NON-COMPETING CONTINUATION	$504,225
														Subtotal = $543,441

Issue Date FY: 2023 ( Subtotal = $575,669 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	4/7/2023	COMPETING CONTINUATION	$597,347
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	19	4/19/2023	COMPETING CONTINUATION	-$21,678
														Subtotal = $575,669

Issue Date FY: 2021 ( Subtotal = $388,572 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	3/17/2021	NON-COMPETING CONTINUATION	$360,530
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	5/18/2021	NON-COMPETING CONTINUATION	$28,042
														Subtotal = $388,572

Issue Date FY: 2020 ( Subtotal = $400,590 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	3/24/2020	NON-COMPETING CONTINUATION	$400,590
														Subtotal = $400,590

Issue Date FY: 2019 ( Subtotal = $400,590 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	3/19/2019	NON-COMPETING CONTINUATION	$400,590
														Subtotal = $400,590

Issue Date FY: 2018 ( Subtotal = $400,590 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	4/18/2018	NON-COMPETING CONTINUATION	$400,590
														Subtotal = $400,590

Issue Date FY: 2017 ( Subtotal = $400,590 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	14	8/15/2017	COMPETING CONTINUATION	$20
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	2/15/2017	COMPETING CONTINUATION	$400,590
2017	2015	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	13	8/15/2017	NON-COMPETING CONTINUATION	-$20
														Subtotal = $400,590

Issue Date FY: 2015 ( Subtotal = $386,287 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	2/20/2015	NON-COMPETING CONTINUATION	$386,287
														Subtotal = $386,287

Issue Date FY: 2014 ( Subtotal = $378,561 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	4/8/2014	NON-COMPETING CONTINUATION	$378,561
														Subtotal = $378,561

Issue Date FY: 2013 ( Subtotal = $366,974 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	11	7/14/2013	NON-COMPETING CONTINUATION	$19,317
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	4/19/2013	NON-COMPETING CONTINUATION	$347,657
														Subtotal = $366,974

Issue Date FY: 2012 ( Subtotal = $386,287 )
2012	2012	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	4/5/2012	NON-COMPETING CONTINUATION	$386,287
														Subtotal = $386,287

Issue Date FY: 2011 ( Subtotal = $409,918 )
2011	2011	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	3/7/2011	COMPETING CONTINUATION	$409,918
2011	2009	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	3/3/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $409,918

Issue Date FY: 2009 ( Subtotal = $318,209 )
2009	2009	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	5/19/2009	NON-COMPETING CONTINUATION	$318,209
														Subtotal = $318,209

Issue Date FY: 2008 ( Subtotal = $318,209 )
2008	2008	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	5/7/2008	NON-COMPETING CONTINUATION	$318,209
														Subtotal = $318,209

Issue Date FY: 2007 ( Subtotal = $324,702 )
2007	2007	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	5/25/2007	NON-COMPETING CONTINUATION	$324,702
														Subtotal = $324,702

Issue Date FY: 2006 ( Subtotal = $335,500 )
2006	2006	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/30/2006	COMPETING CONTINUATION	$335,500
														Subtotal = $335,500

Issue Date FY: 2004 ( Subtotal = $231,000 )
2004	2004	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/30/2004	NON-COMPETING CONTINUATION	$231,000
														Subtotal = $231,000

Issue Date FY: 2003 ( Subtotal = $231,000 )
2003	2003	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/23/2003	NON-COMPETING CONTINUATION	$231,000
														Subtotal = $231,000

Issue Date FY: 2002 ( Subtotal = $231,000 )
2002	2002	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/2/2002	NON-COMPETING CONTINUATION	$231,000
														Subtotal = $231,000

Issue Date FY: 2001 ( Subtotal = $231,000 )
2001	2001	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/13/2001	NEW	$231,000
														Subtotal = $231,000

Grand Total All Awards = $7,762,914

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Response of the Osteoporotic Skeleton to Mechanical Loading

Award Number: R01AR047867

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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