Researchers at Tohoku University of Japan found a possible treatment for a rare bone loss disease called Hajdu-Cheney syndrome, a rare disease that leads to severe osteoporosis and developmental defects. The findings could also help for developing a treatment for age-related osteoporosis.

Hajdu-Cheney syndrome is linked to mutations in NOTCH2, a gene that codes proteins that keep the balance of bone destruction and construction, essential for their maintenance and repair. When NOTCH2 is mutated due Hajdu-Cheney syndrome, this balance is altered causing bone reabsorption. However, the mechanisms of this bone reabsorption were little known so far.

The new study, published in the journal Molecular Cell, focused in a specific molecular pathway associated with this syndrome.  The team of researchers, led by Hiroyuki Inuzuka, found that a specific NOTCH2 mutation that affects this pathway does not maintain abundance of proteins coded by this gene, with the help of another protein called FBW7.

To test their discovery, the team or researchers turn off the gene Fbw7 in mice models, and with it its encoding protein, FBW7.  According to the results, the modified mice presented severe osteoporosis, similar to human Hajdu-Cheney syndrome. The findings then suggest that FBW7 protein is the primary regulator of this system.

Then, in humans with Hajdu-Cheney syndrome, the researchers found that FBW7 protein was not able to bind to NOTCH2 proteins, because the binding spot is missing in osteoclasts (a type of bone cell that breaks down bone tissue) due to the gene mutation.  As a result the osteoclasts over-function, breaking down bone tissue without control.

The Tohoku University researchers gave the mice presenting severe osteoporosis a medication that blocks osteoclast formation, which reversed bone loss. Among the different treatments they tested, they found particularly effective a chemical compound called DAPT, which had showed in previous studies to improve osteoarthritis by inhibiting function of NOTCH proteins.

The reserachers concluded that a treatment with DAPT and Zoledronic acid, a common medication for osteoporosis, “may become a first-line treatment for Hadju-Cheney syndrome.”

By clearly identifying the relationship between FBW7 and NOTCH2 proteins, we have identified potential therapeutic targets for patients with rare bone diseases as well as much more widespread age-related osteoporosis,” said Inuzuka.


Source: Sience Daily