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Osteoclasts or RANKL: Which is the critical target in treatment of fibrous dysplasia bone lesions?

Award Number: R21AR080849
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: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Osteoclasts or RANKL: Which is the critical target in treatment of fibrous dysplasia bone lesions? - Project Summary Fibrous dysplasia (FD) affects approximately 1 in 5000 individuals and causes focal bone lesions that result in pain, deformity and fracture susceptibility. FD lesions are characterized by an accumulation of immature osteoblast lineage cells as well as robust osteoclastogenesis with increased bone turnover. Receptor activator of NFkB ligand (RANKL), the key cytokine driving osteoclast differentiation, is highly expressed by osteoblastic cells in FD lesions. Neutralizing antibody against RANKL, aRANKL, prevents osteoclast formation and decreases lesion size in mouse models of FD. In patients with FD, denosumab, which targets RANKL, is the only effective treatment. However, denosumab can inhibit skeletal growth and withdrawal can cause rebound bone resorption and fractures. Thus, alternative therapies are needed. If we could understand how aRANKL inhibits FD bone lesions, we might be able to discover new treatment targets. To investigate the effect of aRANKL antibody treatment in FD, we used an established mouse model where GnasR201H expression is induced post-zygotically in skeletal stem cells; bone lesions in this model are osteoblastic precursors which are a mosaic of wildtype and lineage traced mutant osteoblastic cells. We demonstrated that aRANKL inhibits the fibrotic bone lesions of FD in this model. At the cellular level, we demonstrated that aRANKL treatment altered the phenotype of Gnas mutant cells and also had a significant impact on wildtype osteoblastic cells, inhibiting proliferation and promoting differentiation of both. The cellular mechanism responsible for the effect of aRANKL is not known. While RANKL is best known for its role in driving osteoclast differentiation, it has many other biologic functions. For example, RANKL is critical for the development of lymph nodes and some specialized epithelial cells, and it can stimulate osteoblast differentiation through reverse signaling. Thus, we hypothesize that RANKL may promote FD bone lesion pathogenesis in an osteoclast-independent manner and that the critical target of aRANKL is RANKL itself. We will test this hypothesis by comparing the efficacy of osteoclast inhibition with anti-CSF1R (which blocks a key survival factor for osteoclasts) with aRANKL in inhibiting FD lesions in this model. The molecular mechanism by which aRANKL treatment alters the cellular phenotype of Gnas mutant cells and wild-type cells in FD lesions is unknown. To investigate the pathways downstream of aRANKL treatment, we propose to determine the transcriptional changes induced in Gnas mutant cells and adjacent wild- type osteoblastic cells using a spatial transcriptomic approach using the GeoMx digital spatial profiler platform. Through a combination of determining whether aRANKL efficacy is independent of osteoclast inhibition and molecular investigation of tissue and cell level response to aRANKL, this proposal will significantly advance our understanding of FD pathogenesis and identify additional pathways that could be targeted for treatment.


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 = $0 )
2026	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $174,545 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/17/2025	NON-COMPETING CONTINUATION	$174,545
														Subtotal = $174,545

Issue Date FY: 2024 ( Subtotal = $228,972 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/1/2024	NEW	$228,972
														Subtotal = $228,972

Grand Total All Awards = $403,517

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Osteoclasts or RANKL: Which is the critical target in treatment of fibrous dysplasia bone lesions?

Award Number: R21AR080849

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: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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