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GROWTH FACTORS; EFFECT ON ASPECTS OF BONE FORMATION

Award Number: R01AR021707
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: 04/01/1981
PERIOD OF PERFORMANCE END DATE: 05/31/2013

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GROWTH FACTORS; EFFECT ON ASPECTS OF BONE FORMATION - DESCRIPTION (provided by applicant): Investigations from our laboratory revealed that Nov, a member of the CCN family of proteins, is expressed by osteoblasts and its transcript levels are regulated by transforming growth factors (TGF) beta and bone morphogenetic proteins (BMP). CCN proteins have been shown to bind and interact with TGF beta, BMPs and Wnt, but the function of Nov in cells of the osteoblastic lineage is not known. Consequently, we explored the function of Nov in skeletal cells, in vitro and in vivo, and found that Nov binds BMPs and determines the cellular fate of undifferentiated stromal cells. Constitutive overexpression of Nov in ST-2 stromal cells resulted in impaired osteoblastic differentiation. Nov overexpression opposed biological effects of BMP-2 and Wnt 3 and impaired BMP-2 and Wnt signaling in ST-2 cells, indicating that Nov has BMP-2 and Wnt antagonistic activity, as it has been reported for classic BMP antagonists. In addition, transgenic mice overexpressing Nov under the control of the osteocalcin promoter exhibited osteopenia secondary to decreased bone formation. The aim of the proposed studies is to understand the function of Nov in bone in vivo and in vitro and define mechanisms involved in its inhibitory effects on osteoblastogenesis and bone formation. For this purpose, we have created transgenic mouse lines overexpressing Nov and created nov null mice. Our specific aims are: 1) To determine the function of Nov in vivo by transgenic overexpression of Nov under the control of the type I collagen or the osteocalcin promoter. The skeletal phenotype of transgenic mice will be compared to that of wild type mice and determined by histomorphometry, contact radiography, densitometry and micro CT scanning; 2) To determine the function of Nov in vivo by targeted gene deletion. The skeletal phenotype will be assessed with histomorphometric, radiological, and structural techniques; and 3) To determine the mechanism of action of Nov in vitro in stromal and osteoblastic cells overexpressing Nov and examining the behavior of nov null cells. The impact of Nov on the differentiation of cells of the osteoblastic lineage and mechanisms involved will be determined. These investigations should clarify the role of Nov in bone cell function, and its interactions with BMP and Wnt signaling pathways.


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: 2012 ( Subtotal = $255,359 )
2012	2012	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	31	5/14/2012	NON-COMPETING CONTINUATION	$255,359
														Subtotal = $255,359

Issue Date FY: 2011 ( Subtotal = $255,359 )
2011	2011	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	30	6/1/2011	NON-COMPETING CONTINUATION	$255,359
														Subtotal = $255,359

Issue Date FY: 2010 ( Subtotal = $265,999 )
2010	2010	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	29	5/31/2010	NON-COMPETING CONTINUATION	$265,999
														Subtotal = $265,999

Issue Date FY: 2009 ( Subtotal = $268,686 )
2009	2009	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	28	6/2/2009	NON-COMPETING CONTINUATION	$268,686
														Subtotal = $268,686

Issue Date FY: 2008 ( Subtotal = $268,686 )
2008	2008	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	27	7/9/2008	COMPETING CONTINUATION	$268,686
														Subtotal = $268,686

Issue Date FY: 2006 ( Subtotal = $209,817 )
2006	2006	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	26	3/22/2006	NON-COMPETING CONTINUATION	$209,817
														Subtotal = $209,817

Issue Date FY: 2005 ( Subtotal = $229,866 )
2005	2005	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	3/21/2005	NON-COMPETING CONTINUATION	$229,866
														Subtotal = $229,866

Issue Date FY: 2004 ( Subtotal = $233,496 )
2004	2004	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	24	3/31/2004	NON-COMPETING CONTINUATION	$233,496
														Subtotal = $233,496

Issue Date FY: 2003 ( Subtotal = $233,496 )
2003	2003	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23		NON-COMPETING CONTINUATION	$233,496
														Subtotal = $233,496

Issue Date FY: 2002 ( Subtotal = $233,496 )
2002	2002	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	22	4/23/2002	COMPETING CONTINUATION	$233,496
														Subtotal = $233,496

Grand Total All Awards = $2,454,260

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GROWTH FACTORS; EFFECT ON ASPECTS OF BONE FORMATION

Award Number: R01AR021707

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: 04/01/1981

PERIOD OF PERFORMANCE END DATE: 05/31/2013

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