Monday, June 30, 2025 6/30/2025

Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

Award Number: R01AR061758
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: 07/01/2011
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome - Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects thousands of children worldwide. HME is characterized by cartilaginous-bony tumors called osteochondromas that form within perichondrium along growth plates and protrude into and collide with surrounding tissues. The tumors can thus cause skeletal deformities, compression of nerves and blood vessels and chronic pain, and become malignant in about 2-3% of patients. Current therapies are limited, and patients struggle with pain and limited mobility and undergo multiple surgeries through life. Most HME patients bear a heterozygous mutation in EXT1 or EXT2 that are responsible for heparan sulfate (HS) synthesis, thus causing a partial systemic HS deficiency. The HS chains -and the proteoglycans of which they are part- regulate and distinctly modulate many processes. Notably, they interact with signaling proteins including bone morphogenetic proteins (BMPs) and hedgehog family members and most often restrict and delimit protein distribution, availability and activity. However, it is not clear whether and which of these mechanisms may be deranged in HME and how it could lead to tumor formation. In the previous funding period, we found that conditional ablation of Ext1 caused an increase in pro-chondrogenic BMP signaling in perichondrium and a concurrent decrease in anti- chondrogenic pERK1/2 and Noggin, deranging normal homeostatic mechanisms that normally maintain the perichondrium phenotype. In preliminary studies, we have aimed to clarify how the osteochondromas acquire a growth plate-like organization, are able to grow unidirectionally against surrounding tissues and thus create damage and havoc. We have obtained evidence for the establishment of an IHH-PTHrP axis driving tumor outgrowth. Our central hypotheses is that osteochondroma development and outgrowth are driven by: (i) a steep local deficiency in HS; (ii) increased BMP signaling; and (iii) establishment of a neo IHH-PTHrP loop. As a result, we posit that osteochondroma development and growth are amenable to drug treatments directed against components of those regulatory circuits. We will use genetic, biochemical and cellular approaches and transgenic mouse models that closely mimic human disease progression and burden. The project will continue to provide fundamentally new insights into cellular and molecular mechanisms of tumor formation as well as normal functioning of those mechanisms in standard perichondrial and growth plate cells. It will also test possible therapies based on those insights and thus has major translational medicine value and implications. The number of HME patients is relatively small, but the community of their families is large. This project will thus provide a renewed sense of hope to patients and families alike that this disease will continue to be actively studied and a cure may one day be found.


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 = $375,584 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	14	5/19/2025	NON-COMPETING CONTINUATION	$27,104
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	3/14/2025	NON-COMPETING CONTINUATION	$348,480
														Subtotal = $375,584

Issue Date FY: 2024 ( Subtotal = $375,584 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	13	8/6/2024	NON-COMPETING CONTINUATION	$27,104
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	3/18/2024	NON-COMPETING CONTINUATION	$348,480
														Subtotal = $375,584

Issue Date FY: 2023 ( Subtotal = $387,200 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	3/28/2023	NON-COMPETING CONTINUATION	$387,200
														Subtotal = $387,200

Issue Date FY: 2022 ( Subtotal = $387,200 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	11	3/30/2022	COMPETING CONTINUATION	$387,200
2022	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	10	7/15/2022	NON-COMPETING CONTINUATION	$0
2022	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	3/17/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,200

Issue Date FY: 2021 ( Subtotal = $358,512 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	5/18/2021	NON-COMPETING CONTINUATION	$25,872
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	1/5/2021	NON-COMPETING CONTINUATION	$332,640
														Subtotal = $358,512

Issue Date FY: 2020 ( Subtotal = $369,600 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	12/20/2019	NON-COMPETING CONTINUATION	$332,640
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	3/31/2020	NON-COMPETING CONTINUATION	$36,960
														Subtotal = $369,600

Issue Date FY: 2019 ( Subtotal = $369,600 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	12/28/2018	NON-COMPETING CONTINUATION	$369,600
														Subtotal = $369,600

Issue Date FY: 2018 ( Subtotal = $369,600 )
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	5/7/2018	NON-COMPETING CONTINUATION	$36,960
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	11/30/2017	NON-COMPETING CONTINUATION	$332,640
														Subtotal = $369,600

Issue Date FY: 2017 ( Subtotal = $369,600 )
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	005	6	7/31/2017	COMPETING CONTINUATION	-$179
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	6	5/23/2017	COMPETING CONTINUATION	$67,444
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	3/17/2017	COMPETING CONTINUATION	$369,600
2017	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/14/2017	NON-COMPETING CONTINUATION	$0
2017	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	5	7/31/2017	NON-COMPETING CONTINUATION	$179
2017	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	5/23/2017	NON-COMPETING CONTINUATION	-$67,444
														Subtotal = $369,600

Issue Date FY: 2015 ( Subtotal = $522,225 )
2015	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/14/2015	NON-COMPETING CONTINUATION	$522,225
														Subtotal = $522,225

Issue Date FY: 2014 ( Subtotal = $515,717 )
2014	2014	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/5/2014	NON-COMPETING CONTINUATION	$515,717
														Subtotal = $515,717

Issue Date FY: 2013 ( Subtotal = $482,636 )
2013	2013	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/13/2013	NON-COMPETING CONTINUATION	$482,636
														Subtotal = $482,636

Issue Date FY: 2012 ( Subtotal = $512,473 )
2012	2012	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/29/2012	NON-COMPETING CONTINUATION	$512,473
														Subtotal = $512,473

Issue Date FY: 2011 ( Subtotal = $513,751 )
2011	2011	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/1/2011	NEW	$513,751
														Subtotal = $513,751

Grand Total All Awards = $5,909,282

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Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

Award Number: R01AR061758

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: 07/01/2011

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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