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Same process discovered to both form skeleton and protect it for life
Date:3/12/2008

teosarcomas compared to that in samples of normal bone.

Specifically, the team observed higher gene expression in cancer samples of Cyclin D1, a Notch signaling partner that drives cell proliferation to create the pool of immature osteoblasts necessary for bone formation. Past human research has observed that 10 percent of osteosarcomas show increased Cyclin D1 gene expression, and the current study suggests that, in a live animal, the proliferative effect of Notch signaling might contribute to bone cancer by triggering cyclin D1. Better understanding of this mechanism may guide future treatment design efforts, researchers said.

In further tests, researchers found that two secretase inhibitors, which shut down Notch signaling, also decreased pathogenic bone cell growth (proliferation) in osteosarcoma cell samples. One of the compounds, DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl 10 ester), is a gamma secretase inhibitor. Gamma secretase snips off the Notch proteins tail (NICD) inside the cell, freeing it to travel to the cell nucleus and influence gene expression, unless DAPT interferes.

Interestingly, DAPT also blocks the action of secretases that snip into fragments the amyloid precursor protein (APP) in brain cells. Some of these cleaved APP fragments clump together to form "plaques" in the brains of patients with Alzheimer's disease that contribute to the death of brain cells. DAPT is currently in Phase II human clinical trials for the treatment of Alzheimer disease.

One theory is that Notch signaling normally maintains the mesenchymal stem cell pool in our bone marrow and inhibits their differentiation into osteoblasts, said Hilton. So for some patients with oteoporosis, we may be able to briefly inhibit Notch signaling to allow more mesenchymal stem cells to differentiate into osteoblasts, creating a larger pool of bone-building cells. The obstacle to this strategy that generating more bone build
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Contact: Greg Williams
Greg_Williams@urmc.rochester.edu
585-273-1757
University of Rochester Medical Center
Source:Eurekalert

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