A fundamental understanding of the molecular mechanism governing osteoblast differentiation is essential for developing novel bone anabolic therapeutics. Physiological Notch signaling has emerged as a critical suppressive mechanism for osteoblast differentiation to ensure a proper pool of mesenchymal progenitors necessary for long-term bone homeostasis. Hyperactivation of NOTCH2 has recently been discover to cause Hajdu-Cheney syndrome (HCS) characterized by childhood osteoporosis, acroosteolysis and wormian bones. Where or not osteoblast or osteoclast defects are the primary cause for the disease has not been established. Moreover, an effective treatment for the disease is currently lacking. Elucidating the cellular basis for the disease and the relationship between NOTCH and other regulators of bone physiology will provide the basis for a rational design of therapeutics. I the current proposal, we test the hypothesis that suppression of osteoblast differentiation by hyperactive NOTCH2 is primarily responsible for HCS, and that stimulation of the bone anabolic WNT pathway may alleviate the bone defects associated with the disease. We further investigate the biochemical basis for the functional antagonism between NOTCH and WNT signaling. Overall, successful completion of this project is expected to provide novel mechanistic insights about the pathogenesis of HCS, and may open new avenues for effective treatments of the disease.

Public Health Relevance

Hajdu-Cheney Syndrome is a rare autosomal dominant disease with early childhood onset. The disease is characterized by general osteoporosis, acroosteolysis and wormian bones. Recent discoveries have revealed that NOTCH2 hyperactivation mutations are responsible for the disease. This proposal is designed to understand the cellular and molecular mechanisms underlying the disease-causing effect of NOTCH2. Research results from this study may open new avenues for effective treatments of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR055923-06
Application #
8639201
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (02))
Program Officer
Chen, Faye H
Project Start
2008-04-01
Project End
2018-08-31
Budget Start
2013-09-16
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$366,723
Indirect Cost
$125,458
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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