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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-C (02))
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Chen, Faye H
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Chen, Jianquan; Long, Fanxin (2014) mTORC1 signaling controls mammalian skeletal growth through stimulation of protein synthesis. Development 141:2848-54
Esen, Emel; Long, Fanxin (2014) Aerobic glycolysis in osteoblasts. Curr Osteoporos Rep 12:433-8
Regan, Jenna N; Lim, Joohyun; Shi, Yu et al. (2014) Up-regulation of glycolytic metabolism is required for HIF1?-driven bone formation. Proc Natl Acad Sci U S A 111:8673-8
Chen, Jianquan; Shi, Yu; Regan, Jenna et al. (2014) Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PLoS One 9:e85161
Chen, Jianquan; Long, Fanxin (2013) ?-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice. J Bone Miner Res 28:1160-9
Regan, Jenna; Long, Fanxin (2013) Notch signaling and bone remodeling. Curr Osteoporos Rep 11:126-9
Long, Fanxin; Ornitz, David M (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5:a008334
Esen, Emel; Chen, Jianquan; Karner, Courtney M et al. (2013) WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab 17:745-55
Cary, Rachel L; Waddell, Seid; Racioppi, Luigi et al. (2013) Inhibition of Caýýýýý/calmodulin-dependent protein kinase kinase 2 stimulates osteoblast formation and inhibits osteoclast differentiation. J Bone Miner Res 28:1599-610
Tu, Xiaolin; Joeng, Kyu Sang; Long, Fanxin (2012) Indian hedgehog requires additional effectors besides Runx2 to induce osteoblast differentiation. Dev Biol 362:76-82

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