Instead, Karsenty discovered that LRP5 acts on serotonin-producing cells in the gut. It blocks an enzyme that converts the amino acid tryptophan to serotonin. The more LRP5, the more the enzyme is blocked, and the less serotonin is made. The gene has no effect, apparently, on brain cells that make serotonin. After the gut releases serotonin into blood, serotonin travels to bone-forming cells and inhibits their growth. “We made mice with the inactivated gene,” Karsenty said, in which “the bone-forming cells are on strike.” The cells simply would not grow and the mice developed severe osteoporosis.

But the bone cells themselves were fine. When Karsenty grew them in the lab, where they were not exposed to serotonin, they developed normally.

That told him that the problem was not in the bone cells but in some molecule in the mice’s circulation. And that, Karsenty says, led him to serotonin. The mice had four to five times more serotonin in their blood than mice without the mutation.

He tested the idea by adding serotonin to normal mouse bone cells in the laboratory. The cells stopped growing. He could even control bone formation in the mice with the mutated gene by giving them a diet deficient in tryptophan, the precursor of serotonin. Without much tryptophan, the mice could not make much serotonin. And their bones grew denser.

Karsenty and his colleagues also did the reverse experiment, making mice with the mutation that causes superdense bones in humans. Those animals, he said, had “amazing bones” that were hard to break, and they did not develop osteoporosis.

... contd.