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Osteocyte CaMKII as a Critical Regulator of Bone Physiology and Anabolism

Award Number: R01AR071614
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: 03/21/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Osteocyte CaMKII as a Critical Regulator of Bone Physiology and Anabolism - PROJECT SUMMARY Bone responds to many signals and cues to regulate its mass and quality. During the last funding period, we identified a pathway by which several bone anabolic agents regulate an important bone effector protein, sclerostin. This regulation of sclerostin occurred at a surprisingly rapid time scale (minutes) in bone cells and occurred via post- translational control of sclerostin protein destruction by the lysosome, prior to changes in gene expression. A central integrator of these bone anabolic cues that converged on sclerostin protein destruction was the serine/threonine kinase, CaMKII. To test the role of CaMKII in vivo in bone anabolism, we generated osteoblast-lineage (OCN-Cre) conditional deletion mice of the two Camk2 genes expressed in the osteoblast-lineage, Camk2d and Camk2g. Prior to these deletions, very little was known about CaMKII signaling in bone cells, and what data did exist suggested only a relatively subtle role in osteoblast differentiation. To our surprise, these conditional knockout mice revealed a severe, post-natal skeletal phenotype that included a large decrease in bone mass in the trabecular and cortical compartments, spanning the appendicular and axial skeleton as well as the skull. In addition to low bone mass, these mice exhibited skeletal fragility, markedly reduced mechanical properties, and a surprising defect in phosphate homeostasis. Given the severity of this phenotype, we were unable to challenge this mouse with bone anabolic cues in vivo, although we did demonstrate defective sclerostin control ex vivo in response to some bone anabolic cues. The severity of this skeletal phenotype on this mouse is on par with the deletion of beta-catenin, a key signal integrator for bone formation, in bone cells, and establishes CaMKII as a fundamentally important pathway controlling bone homeostasis. In this application, our goal is to understand the unexpected role of CaMKII in osteoblast and osteocyte physiology. We will test the hypothesis that CaMKII is a node of convergence that plays an essential role in bone physiology, including phosphate homeostasis, the degradation of sclerostin in response to bone anabolic cues, and the post-translational control of key effector proteins in bone. In three aims, we will examine; disentangle the molecular, cellular and systemic contributions to the severe skeletal phenotypes of the Camk2d and Camk2g conditional knockout mice; and resolve the role of CaMKII as a signaling node regulating sclerostin degradation for bone anabolic signals in vivo. In total, these experiments will provide insight into the unexpectedly severe post-natal skeletal phenotype in Camk2d and Camk2g in bone, provide insight into the major effector proteins driving this multifactorial phenotype, identify the targets of CaMKII action in osteocytes, and answer the unresolved question as to the contribution of this pathway to bone anabolic signals and sclerostin post-translational control.


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 = $341,711 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	6/16/2025	COMPETING CONTINUATION	$341,711
														Subtotal = $341,711

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $336,501 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	8/5/2022	NON-COMPETING CONTINUATION	$30,591
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/7/2022	NON-COMPETING CONTINUATION	$305,910
														Subtotal = $336,501

Issue Date FY: 2021 ( Subtotal = $329,703 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/21/2021	NON-COMPETING CONTINUATION	$329,703
														Subtotal = $329,703

Issue Date FY: 2020 ( Subtotal = $339,900 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/17/2020	NON-COMPETING CONTINUATION	$339,900
														Subtotal = $339,900

Issue Date FY: 2019 ( Subtotal = $339,900 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/26/2019	NON-COMPETING CONTINUATION	$339,900
														Subtotal = $339,900

Issue Date FY: 2018 ( Subtotal = $339,900 )
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/16/2018	NEW	$339,900
														Subtotal = $339,900

Grand Total All Awards = $2,027,615

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Osteocyte CaMKII as a Critical Regulator of Bone Physiology and Anabolism

Award Number: R01AR071614

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: 03/21/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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