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Researchers identify a pharmaceutical target that reverses osteoporosis in mice

Duke University's biomedical engineers discovered a pharmaceutical target that, when activated, can reverse bone degradation caused by osteoporosis in a mouse model of the disease.

“The currently most widely used drugs approved by the FDA for the treatment of osteoporosis can prevent further bone loss, but they do not help restore bone,” said Shini Vargese, professor of biomedical engineering, mechanical engineering and materials science, as well as orthopedics at Duke. ,

“We discovered a biochemical receptor that, when activated, can do both,” added Yu-Ru “Vernon” Shea, a research scientist at the Vargese lab and the first author of the study.

The results will appear online August 21 in the journal Science Advances.

Despite the apparent rigidity, bone is a living tissue that is constantly destroyed and replaced by the body. Osteoporosis occurs when old tissue is lost faster than new tissue can be created, resulting in the bone becoming weak and brittle. This disease affects over 40 million men and women in the United States alone and is most common in older women after menopause.

In 2014, Vargese studied the role of popular biomedical calcium phosphate devices in promoting bone repair and regeneration. She found that the biochemical adenosine acting on the A2B receptor plays a particularly important role in stimulating bone growth. It goes without saying that the lack of a chemical can play a role in the development of osteoporosis, so Vargese decided to find out.

Shini VargeseIn this study, Vargese and her research team studied mice that had their ovaries removed to mimic osteoporosis after menopause. They studied the expression levels of two enzymes that help produce adenosine, as well as the levels of adenosine that spreads between cells. As expected, they found that a lack of estrogen in mice led to a fall in all three.

Researchers then tested whether an increase in adenosine levels in mice would help reverse the ill effects of the disease. But instead of pumping adenosine itself, they injected a non-hormonal small molecule produced by Bayer that activates the A2B receptor.

“The mice that received the drug were completely cured,” said Vargese. "Their bones were as healthy as the control group without osteoporosis."

While the discovery of a pharmaceutical target that can reverse osteoporosis is exciting, creating a small molecule drug that can activate it without side effects is a challenge. Adenosine is produced naturally throughout the body and performs many functions, such as modulating neurons and regulating blood flow in various organs. Researchers cannot simply throw them into the bloodstream to stop bone destruction without side effects.

But with the A2B receptor identified, Vargese and others may start looking for ways to deliver activators to the bones without flooding other areas of the body. For example, one of Vargese’s students begins to learn how to attach adenosine-like molecules to carriers that target bone tissue. Her laboratory also uses a kind of dressing that can deliver growth-promoting drugs directly to damaged or broken bones.

This study was supported by the National Institutes of Health (R01-AR063184, R01-AR071552).

"Dysregulation of extracellular adenosine mediated by ectonucleotidase during postmenopausal bone loss." Yu-Ru V. Shi, Mengkyan Liu, Song Keun Kwon, Masayuki Iida, I Gong, Nivedita Sangaj, Shini Vargese. Science Advances, 2019. DOI: 10.1126 / sciadv.aax1387

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