Scientists made a surprising discovery that bone formation is regulated by levels of gut-derived serotonin, and a gene called Lrp5 controls bone formation by inhibiting serotonin production. Bone is living tissue that constantly rebuilds as old bone tissue is broken down and new bone is formed. The Lrp5 gene had previously been found to be important in bone formation. Mice lacking Lrp5 have low bone mass due to a decrease in bone formation. In people, mutations in this gene are associated with bone diseases, including a form of osteoporosis. However, it was unknown how Lrp5 regulated bone formation, whether it was acting directly on the bone, and what other cellular factors were involved.
To understand how Lrp5 regulates bone formation, scientists first sought to identify factors controlled by Lpr5 by determining whether any genes were turned on or off differently in bones of mice lacking Lpr5 as compared to normal mice. In mice lacking Lpr5, they found that the gene turned on to the greatest extent is involved in serotonin synthesis, and the activity of this gene was also increased dramatically in gut cells. The animals also had abnormally high levels of serotonin. Only about 5 percent of the body’s serotonin is produced in the brain, where it modulates mood, appetite, sleep, and other processes. The other 95 percent is made in the duodenum of the gastrointestinal tract, but the function of this gut-derived serotonin has been a matter of scientific debate.
With these clues about the importance of gut-derived serotonin, the scientists performed a series of experiments in mice to examine serotonin’s role in bone formation. In one experiment, they found that administration of a chemical inhibitor of serotonin synthesis normalized bone formation in mice lacking Lrp5. In another experiment, they discovered that genetically turning off serotonin production in the gut protected against bone loss in a mouse model of menopause (a time period when women are at greater risk for loss of bone density). Overall, the research showed that increasing serotonin levels slowed the formation of new bone, while inhibiting serotonin production promoted it. In addition, the research demonstrated that Lrp5 was not acting directly on the bone, but rather in the gut to regulate production of serotonin, which in turn travels through the body to bone cells to inhibit bone formation. Studies in a small number of people with bone diseases associated with mutations in Lrp5 showed that the patients have abnormal serotonin levels. These preliminary observations suggest that serotonin may also be important in controlling bone formation in people. Most drugs for osteoporosis that are approved for use in people prevent the breakdown of bone, but do not promote the generation of new bone. The discovery that gut-derived serotonin inhibits bone formation in mice and possibly in people suggests that therapies to inhibit serotonin production in the gut, or to block its action on bone, could be a novel means by which to treat or preempt osteoporosis.
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, and Karsenty G: Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135: 825-837, 2008.