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Preventing low-oxygen response stops flare-ups in bone disorder

The discovery, as well as finding three methods to prevent the low-oxygen response causing flare-ups, may lead to methods of treating fibrodysplasia ossificans progressiva.

By Stephen Feller

PHILADELPHIA, May 2 (UPI) -- By finding that oxygen starvation in patients with fibrodysplasia ossificans progressive, or FOP, is responsible for bone growth in muscles, researchers say they may have a method for limiting flare-ups of the rare bone disease.

Researchers found three methods to block a protein triggered by hypoxia, including the cancer drug Gleevec, which they said prevented the bone growth in mice but will require clinical trials before using in humans.

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FOP is a genetic condition caused by a mutation to the bone morphogenetic protein receptor activin receptor A type 1, or ACVR1, making it overactive. During flare-ups of the condition, cells in lesions caused by the mutation become oxygen starved -- triggering the activation of HIF-1α, meant to help cells when in a low-oxygen environment, but in this case causing further lesions and bone growth that can limit motion, breathing and swallowing.

"Our study provides profound insight into the role of cellular hypoxia in FOP flare-ups and shows that cellular oxygen sensing through HIF-1α is a critical regulator of the BMP pathway and heterotopic ossification in FOP," Dr. Frederick Kaplan, a professor of orthopedic molecular medicine at the University of Pennsylvania, said in a press release.

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For the study, published in the Journal of Bone and Mineral Research, the researchers showed lesions in mice with FOP were oxygen-starved and that hypoxia causes the flare-ups.

When the researchers administered drugs -- a method of "silencing the alarm" that HIF-1α's presence in cells sets off -- BMP signaling returned to normal levels, quieting the flare-up.

In the study, the cancer drug imatinib, sold as Gleevec, along with apigenin, a natural substance found in chamomile tea and alcoholic beverages, and a small molecule called PX-478 restored BMP signaling by blocking the over-presence of HIF-1α. The researchers said, however, more work is required before testing the treatment with humans.

"The implications for targeted clinical trials and for compassionate clinical use of HIF-1α inhibitors in the treatment of FOP flare-ups are promising, however we need more data on dosing, duration, timing, rebound, resistance and long-term safety," Dr. Robert Pignolo, an associate professor at the University of Pennsylvania who led the research.

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