Exorcising the very bones

Blocking a long-chain sugar stops tumors developing in genetically susceptible mice . .

Patients with a rare disease that causes the growth of multiple benign bone tumors – multiple hereditary exostoses (MHE) – have few treatment options today other than surgery. And because patients develop a great many of these tumors, that means a lot of surgeries, besides physical therapy and pain management.
MHE affects roughly 1 in 50,000 people and can pose the risk of transformation to deadly sarcoma.
A recent study at the Sanford Burnham Prebys Medical Discovery Institute suggests a way to suppress the formation of these bony tumors, called osteochondromas, that are a hallmark of the disorder. The research, published this week in JCI Insight, could lead to the first drug for patients affected by the disease.
“For years scientists have known MHE is caused by mutations in two genes – EXT1 and EXT2,” Yu Yamaguchi, a professor at SBP, said in a press release. “But we didn’t fully understand how bone growth signaling goes awry in these patients, which is the information we need to devise strategies to prevent, stop or possibly even reverse tumor growth.”
In humans, MHE is caused by a mutation in one of two genes, EXT1 or EXT2. Together, these genes encode an enzyme necessary to produce heparan sulfate – a long sugar chain that facilitates cell signals that direct bone cell growth and proliferation. But when these genes were inactivated in mice just as they are in human MHE patients, the mice failed to develop symptoms of MHE.

In earlier work, Dr. Yamaguchi and his colleagues had decided not to get rid of all the EXT1 genes in the mouse, choosing only to target those in a small fraction of bone cells. This led to the development of a mouse with all the physical manifestations of MHE, such as bony protrusions, short stature and other skeletal deformities.
Working on this established mouse model, the team concluded that overactive bone morphogenic protein (BMP) signaling was the culprit for the development of MHE. BMPs are a group of growth factors that play a fundamental role in embryonic and postnatal bone development. In MHE patients, BMP signaling is significantly enhanced, causing the development of cartilage-capped bone tumors around active areas of bone growth.
“Our team was able to pinpoint stem cells of developing bone as the cell type that gives rise to tumors in MHE,” said Yamaguchi. “These cells are found in the layer of connective tissue that surrounds cartilage, and in MHE, BMP signaling is out of control.”
“Most importantly, using a BMP inhibitor called LDN-193189, we were able to suppress the formation of bone tumors in MHE mice,” he said. “Although the inhibitor we used is a chemical compound designed for research purposes, it nonetheless opens the door for new prospects to develop drugs to treat humans with the disease.”
“For those patients and families that are impacted by MHE, this is a very important study,” said Sarah Ziegler, vice president of the MHE Research Foundation, and whose son Robert also suffers from MHE.
“Today, the only way to address MHE and its consequences is through surgery,” she said. “MHE patients – mostly children – require multiple operations to remove bone tumors and correct bone deformities, and these surgeries and rehabilitation are disruptive to their childhood. Children should spend their days in a classroom, not in the operating room.”
“Our goal is to look for suitable drugs – small molecule BMP inhibitors – that we can refine for efficacy and selectivity for use in humans. We want to develop the first effective therapy to improve the lives of MHE patients,” Yamaguchi said.
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Click here for the full paper
Click here for an informative page on Yamaguchi’s work