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Stem Cell Initiative
BREAKTHROUGH
| The Gutsy Side of Bone |
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| Gerard Karsenty |
The discovery will likely stun researchers in the field, who have thought for years that the skeleton itself controls bone mass. Instead, the new research found that serotonin released by the gut tells cells in the skeleton to slow production of new bone.
The new insight could transform how osteoporosis is treated by giving doctors a way to increase bone mass, not just slow its loss. The findings were reported by Gerard Karsenty, MD, PhD, chair of genetics and development in P&S, in the Nov. 26, 2008, issue of Cell.
Far from being inert, bone constantly undergoes renovation, with some cells responsible for removing old material and other cells responsible for creating new bone. After age 20, the balance between bone formation and bone breakdown tips toward breakdown, and bone mass starts to decline. Osteoporosis occurs when bone mass drops so much that bones become fragile and porous, increasing the risk of breaks.
Most osteoporosis drugs, including those currently under clinical investigation, do not generate new bone but prevent the breakdown of old bone. Only one drug currently on the market can generate new bone, but because of reports that it may increase the risk of bone cancer, it is restricted for short-term use in women with severe osteoporosis.
“The lack of safe bone-promoting drugs is a major concern because osteoporosis is often diagnosed when the damage to bone is already significant and fracture risk is already too high,” Dr. Karsenty says. “We need something to build bone, not just prevent its loss.”
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| Courtesy of International Business Machines Corporation. Unauthorized use not permitted. |
| Insight into the gut's control over bone growth may lead to new ways to increase bone mass in people with osteoporosis, not just slow bone loss. The CT scans above show normal and osteoporotic bone. |
Like most other bone researchers, Dr. Karsenty and his lab were searching for new ways to build bone by trying to understand a gene called Lrp5. Scientists believe Lrp5 plays a central role in new bone formation because some mutations in the gene cause unusually strong bones. (The condition is usually picked up by dentists after they attempt, and fail, to extract teeth.)
For several years, Dr. Karsenty and other scientists thought Lrp5 worked inside bone cells. But a mistake in his lab serendipitously led the Columbia scientists to the gastrointestinal tract, where 95 percent of the body’s serotonin is produced. It was then that the researchers discovered that Lrp5 controls serotonin production in the gut, and that serotonin from the gut inhibits the creation of new bone.
Whether or not serotonin-based drugs are found for osteoporosis, Dr. Karsenty says he has new respect for the uncalcified parts of the human anatomy. “That a vital control of bone proliferation stems from the gut is amazing and it gives pause to those in my field who did not give the gut its due examination or the credit it deserves for how much it controls in the body,” Dr. Karsenty says. “And that includes me.”
This research was supported by grants from the March of Dimes Foundation and the National Institutes of Health.
