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Demystify Heparan Sulfate–Sclerostin Interactions in Bone Formation

Award Number: R03DE031838
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 10/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Demystify Heparan Sulfate–Sclerostin Interactions in Bone Formation - Project Summary Sclerostin is a potent inhibitor of bone formation and has been shown to be a valuable drug target for treating osteoporosis. Mechanistically, sclerostin functions by binding to LRP5/6 on the osteoblast lineage cells to antagonize canonical Wnt signaling, thus negatively regulates bone formation. Presumably, after sclerostin is secreted by osteocytes, they reach the target osteoblasts at the bone surfaces by diffusion. However, to date it remains unknown how secreted sclerostin is regulated on the cell surface and in the extracellular matrix. To address this significant gap in sclerostin biology, we focus our study on sclerostin–heparan sulfate (HS) interaction. HS, a universal glycosaminoglycan found at the cell surface and in the extracellular matrix, is known to bind sclerostin and might regulate the bioactivity and diffusion of sclerostin. Our central hypothesis is that HS can regulate the biological functions of sclerostin in bone formation. To test this hypothesis, our overall objective here is to elucidate how HS interacts with sclerostin and how HS–sclerostin interaction regulates bone formation. We plan to pursue the following two specific aims: Aim 1. Determine the biological significance of HS–sclerostin interactions in vitro. We postulate that HS helps concentrate sclerostin on the osteoblast cell surface and facilitates the binding of sclerostin to its receptor LRP5/6 by forming ternary complex. We also hypothesize that HS serves a storage depot of sclerostin on the cell surface of osteocytes after it is secreted, and protects it from proteolytic degradation. We will manipulate HS–sclerostin interactions biochemically at the surface of both osteoblasts and osteocytes to determine the mechanisms by which HS regulates the function of sclerostin in these cellular contexts. Aim 2. Determine the role of HS–sclerostin interaction in bone formation in vivo. Our working hypothesis is that dampening HS–sclerostin interactions impairs the inhibitory potency of sclerostin towards LRP5/6, which leads to enhanced bone formation. Using a novel sclerostin knock-in mouse strain, we will examine the consequence of altering HS–sclerostin interactions in bone formation in vivo. Our contribution will be significant because we will identify multiple molecular mechanisms by which HS regulates sclerostin and elucidate how such interactions regulate bone formation. Results from the proposed experiments will substantially advance our understanding of the cellular regulation of sclerostin on both osteoblasts and osteocytes by elucidating the role of HS in the system. Importantly, these results are expected to have positive translational impact because by identifying how HS regulates the bioavailability of sclerostin, we may be able to provide new perspective for manipulating sclerostin in bone diseases.


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 = $0 )
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	003	3	3/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$10,972
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	001	3	12/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$64,066
2025	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	2	12/19/2024	NON-COMPETING CONTINUATION	-$64,066
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	002	2	3/24/2025	NON-COMPETING CONTINUATION	-$10,972
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $159,500 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	2	2/5/2024	NON-COMPETING CONTINUATION	$143,550
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	001	2	5/30/2024	NON-COMPETING CONTINUATION	$15,950
														Subtotal = $159,500

Issue Date FY: 2023 ( Subtotal = $159,500 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	1	1/30/2023	NEW	$159,500
														Subtotal = $159,500

Grand Total All Awards = $319,000

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Demystify Heparan Sulfate–Sclerostin Interactions in Bone Formation

Award Number: R03DE031838

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 10/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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