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Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

Award Number: R01AR071463
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: 04/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J - Osteoclasts are responsible for bone resorption not only in physiological bone development and remodeling, but also in diseases characterized by inflammatory osteolysis, such as rheumatoid arthritis (RA). Inflammatory bone resorption is complex and resistant to standard anti-resorptive therapies. Moreover, current treatments of osteolysis often cause long-term side effects, including bone remodeling/repair defects and/or immunosuppression. Therefore, there is an important medical unmet need to discover new mechanisms that predominantly or selectively regulate inflammatory osteoclastogenesis, minimizing undesirable effects on bone remodeling or immune response in disease settings. These mechanisms are much less understood. We have focused particular attention on TNF-mediated osteoclastogenesis and bone destruction since TNF is a key pathogenic factor driving inflammatory bone resorption. In the previous project period, we identified the transcription repressor RBP-J as a crucial negative regulator that prominently restrains TNF-induced osteoclastogenesis and inflammatory bone resorption, but not RANKL-induced osteoclastogenesis and bone remodeling. However, the downstream targets of RBP-J specifically involved in TNF-mediated osteoclastogenesis are not well understood. In this application, we identified Hs2st1 as a direct RBP-J target in TNF-induced osteoclastogenesis. Hs2st1 is a heparan sulfate (HS) biosynthetic enzyme that adds sulfate to the 2-O-position of the HS chain on cellular surface. HS sulfation mediated by Hs2st1 affects the interaction between HS and their binding proteins, thereby modulating various cellular activities. RBP-J deficiency enables TNF to turn on the expression of Hs2st1 in osteoclast differentiation. However, the function of and mechanisms mediated by Hs2st1 in osteoclastogenesis, especially in inflammatory settings, are unclear. We found that both RBP-J and Hs2st1 predominantly regulate TNF-induced, but minimally affect RANKL-induced osteoclastogenesis and basal bone mass. Based on our preliminary results, in this proposal, we will 1) investigate the role of Hs2st1 and RBP- J-Hs2st1 axis in vivo in inflammatory bone resorption using genetic approaches, and 2) investigate the mechanisms by which Hs2st1 promotes TNF-induced osteoclastogenesis. We found that Hs2st1 suppresses TNF-induced endogenous IFNβ pathway, a key autocrine feedback inhibitory loop for osteoclastogenesis. Thus, we will primarily focus on the regulation of IFNβ pathway by Hs2st1 in this aim. Successful completion of the proposed studies will establish a novel paradigm wherein a previously unrecognized network mediated by RBP-J, RBP-J new target Hs2st1, HS and HS specific binding proteins specifically governs inflammatory osteoclastogenesis. Since this network appears not to impact physiological osteoclastogenesis and bone remodeling, the players and mechanisms identified in this paradigm will provide a rational framework for developing attractive therapeutic approaches for suppressing inflammatory bone resorption, minimizing side effect on bone remodeling/repair.


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 = $668,992 )
2025	2025	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	6/4/2025	NON-COMPETING CONTINUATION	$48,277
2025	2025	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	12/18/2024	NON-COMPETING CONTINUATION	$620,715
														Subtotal = $668,992

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	5/20/2024	COMPETING CONTINUATION	$0
2024	2021	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	9/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $710,498 )
2023	2023	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/20/2023	COMPETING CONTINUATION	$710,498
														Subtotal = $710,498

Issue Date FY: 2021 ( Subtotal = $375,584 )
2021	2021	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/18/2021	NON-COMPETING CONTINUATION	$348,480
2021	2021	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/7/2021	NON-COMPETING CONTINUATION	$27,104
														Subtotal = $375,584

Issue Date FY: 2020 ( Subtotal = $387,200 )
2020	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/20/2020	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2019 ( Subtotal = $387,200 )
2019	2019	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/3/2019	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2018 ( Subtotal = $387,200 )
2018	2018	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/14/2018	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2017 ( Subtotal = $387,200 )
2017	2017	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/17/2017	NEW	$387,200
														Subtotal = $387,200

Grand Total All Awards = $3,303,874

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Regulation of Osteoclastogenesis and Arthritic Bone Resorption by RBP-J

Award Number: R01AR071463

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: 04/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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