By: Madeline Ellis
healthnews.com

Through a process called remodeling, our body continuously breaks down bone, absorbs it and then rebuilds it. During the first three decades of our lives, bone is deposited faster than it is used, but by about age 30, breakdown outpaces formation and bone density declines, often resulting in osteoporosis, a condition that makes the bones weak and more likely to break. According to estimates, osteoporosis was responsible for more than 2 million fractures in 2005, with that number expected to rise as the population ages. There is no cure for osteoporosis, and most of the drugs currently approved for the treatment of the disease act by slowing the turnover of bone, rather than stimulating new bone formation. However, an accidental discovery may open the door for new treatments for the disease, which currently affects nearly 10 million Americans over the age of 50.

While investigating the role of a protein known as LDL-receptor related protein 5, or LRP5, in two rare forms of osteoporoses, a team of researchers led by Dr. Gerard Karsenty, chairman of the department of genetics and development at the Columbia University College of Physicians and Surgeons in NewYork, discovered that bone formation is controlled through serotonin produced by the duodenum, a part of the gastrointestinal tract. Ninety-five percent of the body’s serotonin is made by the gut, while the brain generates the other five percent. A membrane blocks serotonin made in the gut from entering the brain, but gut serotonin is released into the blood where it travels to bone-forming cells and inhibits their growth. The more serotonin that reaches the bone, the more bone loss; the less serotonin, the denser and stronger the bones become. “This is totally new,” Dr. Karsenty said. “We had no clue that the gut had control over bone, and in such a powerful manner.”

LRP5 acts on serotonin-producing cells in the gut by blocking the enzyme that converts the amino acid tryptophan to serotonin. The more LRP5, the more the enzyme is blocked and the less serotonin is made. To test the link between LRP5 and gut serotonin, the researchers gave mice mutations that caused a reduction in LRP5 activity. These mice had much higher levels of gut serotonin than the mice without the mutation. The same was true of three human patients who had osteoporosis caused by the mutations in the LRP5 gene; they had four-to-five times the gut-derived serotonin than that of age-matched control subjects.

Conversely, mice with mutations that caused an increase in LRP5 protein activity, causing dense bones, had lower levels of gut-derived serotonin. Two human patients with high bone mass syndrome caused by similar mutations were found to have half the gut-derived serotonin than their control subjects. Until these experiments, the function of gut-associated serotonin was not known, Dr. Karsenty said. “The findings demonstrate without a doubt that serotonin from the gut is acting as a hormone to regulate bone mass.”

The researchers were able to change the density of the mice’s bones by manipulating the serotonin levels in the gut. As a way to lower the levels of gut-derived serotonin, the mice were fed a diet low in tryptophan. On this low-tryptophan diet, mice with the mutation that would have caused weak bones had normal bone density. Mutated mice that received a drug that prevents serotonin synthesis in the gut had the same outcome as the ones on the low-tryptophan diet. The researchers were also able to prevent osteoporosis in mice undergoing menopause by shutting off the gut’s release of serotonin. Although the findings were made on mice, Dr. Karsenty says they help to understand bone modeling in humans. “This is not a mouse story,” he said. “From the beginning it was a human story that we have worked out in the mouse.”

These findings open vast possibilities of controlling diseases such as osteoporosis, either by a diet low in tryptophan or by inhibiting serotonin synthesis with medications. Dr. Karsenty said he thinks since the cells that produce serotonin come into contact with drugs that pass through the gastrointestinal tract, reducing gut-derived serotonin should be relatively simple to achieve with a drug, with few side effects. “The lack of bone promoting drugs is a major concern because osteoporoses is often diagnosed when the damage to bone is already significant and fracture risk is already too high,” said Dr. Karsenty. “We need something to build bone, not just prevent or repair its loss.”

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