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Biology of cortical bone of long bones and calvarium: Role of Sfrp4 in periosteal bone formation

Award Number: R01DE029615
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: 05/08/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Biology of cortical bone of long bones and calvarium: Role of Sfrp4 in periosteal bone formation - The periosteum plays a critical role in cortical bone expansion and homeostasis, has regenerative capabilities and responds to anabolic drugs. However, in spite of its clinical significance our basic understanding of periosteal cellular characteristics, local or paracrine regulatory factors as well as the specific mechanisms by which anabolic drugs regulate it, remain elusive. Thanks to powerful new sequencing technologies, a periosteal population of cells labeled by Cathepsin K (Ctsk+), which includes bona fide periosteal stem cells (PSCs) and non-stem periosteal progenitor (PP1 and PP2) cells has been recently identified in the long bones and calvarium, providing a great opportunity for studying the regulation and physiological relevance of the periosteum in skeletal phenotypes. In this context, our recent studies have established that loss of function mutations of the Wnt inhibitor SFRP4 lead to Pyle’s disease, a rare skeletal disease characterized by limb deformity and fragility fractures. Using the Sfrp4-/- mouse model we uncovered that Sfrp4 contributes to cortical bone expansion and homeostasis by regulating endosteal remodeling and periosteal formation. The studies proposed here are focused on the biology of the periosteal surface. Our objective is to identify the role of Sfrp4-mediated signaling in regulating its activity. We have found that Sfrp4+ cells in the periosteum constitute a specific pool of Ctsk+ “periosteal” progenitors (PP1 and PP2) and that Sfrp4 deletion alters the % of PSCs and PP2 cells. The goal of the studies proposed in Aim 1 is to address whether Sfrp4 regulates the expansion, differentiation and/or function of periosteal stem cells and progenitors and the mechanisms by which this occurs. Given that PTH is a potent stimulator of periosteal bone formation, the findings that PSCs, bona fide stem cells, express the PTH receptor together with the findings that PTH positively regulates Sfrp4 in the periosteum are of significance and may have clinical consequences for the treatment of Pyle’s disease patients. The goal of the studies proposed in Aim 2 is therefore to explore whether Sfrp4-Wnt mediated signaling cooperate with PTH to regulate periosteal formation. Compelling evidences have demonstrated that stem cells in the calvarium suture and periosteum serve as growth centers for bone formation during development and support bone repair in response to injury. In the calvarium PSCs are mainly within the suture, while PP2 cells are predominant in the calvarial periosteum outside of the suture and PP1 are found at both sites. Despite canonical and non-canonical Wnt signaling activation, the absence of Sfrp4 results in lack of new bone formation in response to injury. The goal of the studies proposed in Aim 3 is to explore the mechanism(s) by which Sfrp4+ cells contribute to the bone regenerative potential of stem cells/progenitors using calvarial defects as injury repair model. Analysis of signaling pathways regulating periosteal stem cells and progenitors may open novel and specific therapeutic options for human diseases associated with bone fragility and impaired bone healing and bone regeneration.


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: 2027 ( Subtotal = -$370 )
2027	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	5	10/13/2026	NON-COMPETING CONTINUATION	-$370
														Subtotal = -$370

Issue Date FY: 2024 ( Subtotal = $394,423 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	5	4/16/2024	NON-COMPETING CONTINUATION	$362,224
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	001	5	6/18/2024	NON-COMPETING CONTINUATION	$32,199
														Subtotal = $394,423

Issue Date FY: 2023 ( Subtotal = $402,564 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	4	4/12/2023	NON-COMPETING CONTINUATION	$402,564
														Subtotal = $402,564

Issue Date FY: 2022 ( Subtotal = $398,538 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	3	4/6/2022	NON-COMPETING CONTINUATION	$362,307
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	001	3	4/28/2022	NON-COMPETING CONTINUATION	$36,231
														Subtotal = $398,538

Issue Date FY: 2021 ( Subtotal = $402,564 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	2	4/22/2021	NON-COMPETING CONTINUATION	$402,564
														Subtotal = $402,564

Issue Date FY: 2020 ( Subtotal = $402,564 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	5/7/2020	NEW	$402,564
														Subtotal = $402,564

Grand Total All Awards = $2,000,283

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Biology of cortical bone of long bones and calvarium: Role of Sfrp4 in periosteal bone formation

Award Number: R01DE029615

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: 05/08/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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