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Osteoclast-Osteocyte Interaction's in Paget's Disease

Award Number: R01AR080116
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: 02/22/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Osteoclast-Osteocyte Interaction's in Paget's Disease - Project Summary/Abstract: Paget’s Disease (PD) is usually diagnosed in patients >50 years of age, and is characterized by focal bone lesions (PDLs) that progress from an initial lytic to a mixed osteolytic-osteoblastic phase, due to rapid new bone formation. PD patients rarely develop new PDLs beyond those present at diagnosis. The primary cellular abnormality in PD resides in the osteoclast (OCL). However, the mechanisms responsible for the highly focal nature of PDLs, why PD is diagnosed in elderly patients, especially in patients harboring genetic mutations linked to PD, and the mechanisms driving the exuberant resorption/formation in PD, are unclear. We showed that OCLs from 70% of PD patients express measles virus nucleocapsid protein (MVNP), and transgenic mice with MVNP targeted to OCLs (MVNP mice) develop PDLs and the abnormal OCLs characteristic of PD. MVNP- expressing OCLs and OCLs from PD patients are hyper-responsive to RANKL and express high IL-6 levels, which induce high levels of IGF1 in OCLs (OCL-IGF1) to promote osteoblast (OB) differentiation in MVNP mice. Importantly, OCLs from PD patients but not normal donors also express increased IL-6 and IGF1. We confirmed OCL-IGF1’s role in PD and normal bone remodeling in vivo by generating WT and MVNP mice with targeted deletion of Igf1 in OCLs. We found that MVNP mice but not MVNP mice lacking OCL-Igf1 developed PDLs. Thus, high OCL-IGF1 levels in PD may be required to induce PDLs. However, these results do not explain why PDLs occur in aging patients or animal models and persist locally for long periods. These observations are most readily explained by stochastic changes in a long-lived bone cell population, most likely osteocytes (OCys). In this proposal we will test the Hypothesis: that pagetic OCL precursors, which are hyper-responsive to RANKL, home to specific skeletal sites containing senescent, pre-lesional OCys that produce or induce locally increased RANKL. As PD-OCLs numbers increase, they hyper-secrete sufficient IL-6 and IGF-1 to decrease Sost/sclerostin, increase expression of Wnts, block OCy differentiation and act directly on OB to enhance new bone formation. In preliminary studies, we found that OCys in PD (PD-OCys) express lower levels of OCy maturation markers, and display markedly reduced dendritic processes. Further, the percentage of sclerostin+ OCys adjacent to PDLs in MVNP mice was significantly lower compared to MVNP mice without PDLs or WT mice, and that IGF1 suppressed sclerostin expression in OCys. Importantly, similar morphologic changes occurred in OCys in bone samples of a PD patient, but not a normal donor. These results suggest that OCys may be key contributors to the pathogenesis of PD. To further test this hypothesis, we will: Aim 1. Characterize OCL-IGF1’s effects in PD and PD-OCys, identify the molecular mechanisms involved, and test if increased OCL-IGF1 is sufficient to induce PDLs and PD-OCys. Aim 2. Determine the role of senescent OCys in the location, development, progression and persistence of PDLs and PD. We will assess if prolonged exposure of PD-OCLs to normal OCys, or shorter exposure to OCys in older mice suffices for PDLs to develop.


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 = $457,457 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/4/2026	NON-COMPETING CONTINUATION	$24,077
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/7/2026	NON-COMPETING CONTINUATION	$433,380
														Subtotal = $457,457

Issue Date FY: 2025 ( Subtotal = $467,734 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/12/2024	NON-COMPETING CONTINUATION	$433,980
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/4/2025	NON-COMPETING CONTINUATION	$33,754
														Subtotal = $467,734

Issue Date FY: 2024 ( Subtotal = $468,362 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/10/2024	NON-COMPETING CONTINUATION	$434,564
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	7/3/2024	NON-COMPETING CONTINUATION	$33,798
														Subtotal = $468,362

Issue Date FY: 2023 ( Subtotal = $485,083 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/14/2023	NON-COMPETING CONTINUATION	$436,575
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	6/22/2023	NON-COMPETING CONTINUATION	$0
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/23/2023	NON-COMPETING CONTINUATION	$48,508
														Subtotal = $485,083

Issue Date FY: 2022 ( Subtotal = $526,359 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/22/2022	NEW	$526,359
														Subtotal = $526,359

Grand Total All Awards = $2,404,995

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Osteoclast-Osteocyte Interaction's in Paget's Disease

Award Number: R01AR080116

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: 02/22/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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