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Osteocyte Calcium and Contractile Dynamics in Facilitating the Expression of RANKL, OPG, and Sclerostin under Mechanical Loading

Award Number: R01AR069148
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: 09/19/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Osteocyte Calcium and Contractile Dynamics in Facilitating the Expression of RANKL, OPG, and Sclerostin under Mechanical Loading - Osteocytes are mechanosensors in bone with an ability to control bone resorption and formation through the expression of RANKL and sclerostin, respectively. However, the mechanisms by which osteocytes convert local mechanical cues to chemical signals across the lacunocanalicular system (LCS) and to the bone surface remain unclear. Ca2+ dynamics are a hallmark response of osteocytes to mechanical loading, but few studies have explored the role of Ca2+-dependent events in osteocyte mechanotransduction. Preliminary studies from our laboratory have uncovered novel Ca2+-dependent events that could contribute to bone adaptation. We discovered that mechanical loading induces Ca2+-dependent actomyosin contractions in osteocytes and that flow-induced Ca2+ oscillations facilitate the release of extracellular vesicles (EVs) containing RANKL, OPG and sclerostin. We therefore hypothesize that mechanically-induced Ca2+/actomyosin dynamics spatially and temporally regulate key proteins to direct bone formation and resorption responses to mechanical loading. To test this hypothesis, we have designed specific aims that leverage multi-scale approaches to evaluate the relative influence of Ca2+ oscillations and actomyosin contractility on osteocyte protein expression using a combination of loading regimens and antagonists. In particular, we focus on RANKL, OPG, and sclerostin, as mechanisms underlying the mechanical modulation of these proteins remain unknown. Specific Aim 1: Simultaneously monitor Ca2+ and actin strains in quasi-3D and 2D networks of osteocytes subjected to various fluid shear conditions and measure EV release and gene/protein expression of RANKL, OPG, and sclerostin in the presence or absence of inhibitors for Ca2+ and actomyosin contractile pathways. Specific Aim 2: Simultaneously monitor Ca2+ and actin strains in osteocytes in ex vivo mouse tibiae subjected to various mechanical loads and quantify the short-term spatial distribution of EVs in the 3D osteocyte LCS in the presence or absence of inhibitors for Ca2+ and actomyosin contractile pathways. Specific Aim 3: Examine spatial and temporal protein expression of RANKL, OPG, and sclerostin in osteocytes and their relationship to EV markers and cross-sectional strain and periosteal/endosteal bone formation/resorption dynamics in mouse tibiae in vivo subjected to various mechanical loading conditions and antagonists for Ca2+ and actomyosin contractile pathways. We expect to demonstrate that Ca2+-induced actomyosin contractions and facilitated vesicle release is an important mechanism in the translation of mechanical loading to early biochemical responses and later bone adaptation. A better understanding of osteocyte mechanotransduction may improve our ability to prevent bone degeneration in diseases such as osteoporosis where this function is impaired. Furthermore, understanding how proteins like RANKL, OPG, and sclerostin are expressed under various conditions can inform the use of therapeutics targeting their expression and help optimize treatment strategies.


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: 2022 ( Subtotal = -$1,143 )
2022	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/22/2021	NON-COMPETING CONTINUATION	-$1,143
														Subtotal = -$1,143

Issue Date FY: 2020 ( Subtotal = $347,958 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/10/2020	NON-COMPETING CONTINUATION	$347,958
														Subtotal = $347,958

Issue Date FY: 2019 ( Subtotal = $346,397 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/15/2019	NON-COMPETING CONTINUATION	$346,397
														Subtotal = $346,397

Issue Date FY: 2018 ( Subtotal = $344,880 )
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/27/2018	NON-COMPETING CONTINUATION	$344,880
														Subtotal = $344,880

Issue Date FY: 2017 ( Subtotal = $343,407 )
2017	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/21/2017	NON-COMPETING CONTINUATION	$343,407
														Subtotal = $343,407

Issue Date FY: 2016 ( Subtotal = $341,978 )
2016	2016	COLUMBIA UNIVERSITY	615 WEST 131ST ST, 4TH FLOOR	NEW YORK	NY	10027	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/16/2016	NEW	$341,978
														Subtotal = $341,978

Grand Total All Awards = $1,723,477

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Osteocyte Calcium and Contractile Dynamics in Facilitating the Expression of RANKL, OPG, and Sclerostin under Mechanical Loading

Award Number: R01AR069148

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: 09/19/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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