Previous investigations from our laboratory revealed that Notch is expressed by osteoblasts and its synthesis is regulated by glucocorticoids. Notch plays a critical role in osteoblastogenesis and its deletion results in serious developmental defects and neonatal lethality. Its over expression in the skeleton causes osteopenia secondary to an inhibitory effect on osteoblastogenesis. Although the activation of the canonical Notch signaling pathway induces the expression of hairy enhancer of split (HES)-1, HES-1 over expression does not recapitulate all the effects of Notch, and alternate signals, such as HEY-1 also play a role in the inhibitory effects of Notch in cells of the osteoblastic lineage. Central to the inhibitory actions of Notch is the suppression of the Wnt/?-catenin signaling pathway.
The aim of the proposed studies is to understand the function of Notch and HES-1 in bone in vivo and in vitro and define mechanisms involved. For this purpose, we will use transgenic mouse lines over expressing Notch or HES-1 in the bone environment, and mice carrying conditional deletions of notch1 and 2 or hes-1.
Our specific aims are: 1) To explore the mechanism of action of Notch in cells of the osteoblastic lineage, particularly mechanisms involved in its inhibitory effects on Wnt/?-catenin;2) To determine the function of HES-1 in vivo by transgenic over expression of HES-1 under the control of the type I collagen promoter, and by targeted hes-1 conditional deletion. The skeletal phenotype of mice misexpressing HES-1 will be compared to that of wild type mice and determined by histomorphometry, contact radiography, densitometry and micro CT scanning;and 3) To determine the mechanism of action of HES-1 in vitro and signals responsible for its effects on osteoblastogenesis. The impact of Notch and HES-1 on bone remodeling and mechanisms involved will be determined. These investigations should clarify the role of Notch and HES-1 in bone cell function.

Public Health Relevance

This project will provide novel information on intracellular proteins that regulate the function of bone forming cells, and is relevant to our understanding of mechanisms involved in osteoporosis and developments of new therapies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045227-18
Application #
8079029
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Malozowski, Saul N
Project Start
1991-09-30
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
18
Fiscal Year
2011
Total Cost
$294,391
Indirect Cost
Name
St. Francis Hospital and Medical Center
Department
Type
DUNS #
077314656
City
Hartford
State
CT
Country
United States
Zip Code
06105
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Canalis, Ernesto (2018) MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis. Eur J Endocrinol 178:R33-R44
Canalis, Ernesto (2018) Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism 80:48-56
Yu, Jungeun; Zanotti, Stefano; Walia, Bhavita et al. (2018) The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the Splenic Marginal Zone. Am J Pathol 188:149-159
Canalis, Ernesto; Yu, Jungeun; Schilling, Lauren et al. (2018) The lateral meningocele syndrome mutation causes marked osteopenia in mice. J Biol Chem 293:14165-14177
Zanotti, S; Yu, J; Bridgewater, D et al. (2018) Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis. Bone 114:198-205
Canalis, Ernesto; Sanjay, Archana; Yu, Jungeun et al. (2017) An Antibody to Notch2 Reverses the Osteopenic Phenotype of Hajdu-Cheney Mutant Male Mice. Endocrinology 158:730-742
Zanotti, Stefano; Canalis, Ernesto (2017) Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes. Bone 103:159-167
Canalis, Ernesto; Zanotti, Stefano (2017) Hairy and Enhancer of Split-Related With YRPW Motif-Like (HeyL) Is Dispensable for Bone Remodeling in Mice. J Cell Biochem 118:1819-1826
Zanotti, Stefano; Yu, Jungeun; Sanjay, Archana et al. (2017) Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome. J Biol Chem 292:12232-12244

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