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Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways

Award Number: R01AR079246
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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Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways Summary Osteocyte death, one of the hallmarks of skeletal aging, contributes to the age-related decline in bone strength and the increase in age-related fractures. In addition to aging, many other factors also lead to osteocyte death, including unloading, sex hormone deficiency, glucocorticoid excess, inflammation, and osteoarthritis. Although osteocytes function as master regulators of bone remodeling, the underlying molecular mechanisms that sustain osteocyte viability are poorly understood. Our studies aim to fill a gap in knowledge on endogenous factors that maintain osteocyte viability and bone quality in adult bone, as this is paramount to maintaining bone health. This proposal examines a novel role for Fibroblast Growth Factor Receptor (FGFR) signaling in the maintenance of osteocyte viability and skeletal homeostasis. In a recent publication, we identified a novel requirement for FGFR signaling for osteocyte survival. We showed that conditional knockout of FGFRs in mature osteoblasts and osteocytes led to osteocyte death in juvenile (3-week-old) mice and secondarily, increased bone mass as these mice aged. In a preliminary follow-up study, we temporally inactivated FGFRs in osteoblasts and osteocytes in adult (12-week-old) mice to bypass any effects on developing or actively growing bone. This also resulted in osteocyte death after several weeks and increased bone mass after several months. These observations form the basis of our hypothesis that in mature adult bone, FGFR signaling is required for maintaining osteocyte viability and bone homeostasis. Our proposed studies will address the mechanisms by which FGFR signaling maintains osteocyte viability and skeletal homeostasis in adult mice. Using lineage tracing and anabolic loading we will determine whether existing osteocytes vs newly formed osteocytes are sensitive to loss of FGFR signaling. In vivo analysis will identify the primary mode of cell death and determine whether remodeling of the osteocyte lacunocanalicular system is a cause or a consequence of loss of osteocyte viability. In vitro analysis of osteocyte cell lines will determine if FGFR signaling pathways are required cell-autonomously for osteocyte viability. Our preliminary data also suggests potential clinically relevant circumstances for either gain- or loss-of- function of FGFR signaling in bone. Two FDA approved FGFR inhibitors (Erdafitinib, Pemigatinib) have a median treatment period of 5 months for cancer. Our studies suggest that prolonged treatment with FGFR inhibitors could affect bone homeostasis. We will thus test the effects of Erdafitinib on osteocyte viability and biomechanical properties of bone in adult and aged mice. Finally, we will determine whether activation of FGFR signaling in mature osteoblasts and osteocytes is protective under conditions that promote osteocyte death. Completion of these studies will establish a role and identify mechanisms for FGFR signaling in the maintenance of osteocyte viability and bone homeostasis in adults, they will evaluate potential adverse effects of FGFR inhibition on bone, and will identify new genes that could be targeted to promote skeletal homeostasis.


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: 2024 ( Subtotal = $471,694 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/22/2024	NON-COMPETING CONTINUATION	$471,694
														Subtotal = $471,694

Issue Date FY: 2023 ( Subtotal = $524,103 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/1/2023	NON-COMPETING CONTINUATION	$471,694
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/28/2023	NON-COMPETING CONTINUATION	$52,409
														Subtotal = $524,103

Issue Date FY: 2022 ( Subtotal = $524,103 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/21/2022	NEW	$524,103
														Subtotal = $524,103

Grand Total All Awards = $1,519,900

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Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways

Award Number: R01AR079246

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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