In research being hailed as groundbreaking, a team of researchers led by Dr. Gerard Karsenty at Columbia University has discovered an unlikely partner in the fight against bone disease: your gut. Exciting new research shows that a signal released by the gut can regulate the bone cells that strengthen bone tissue. Scientists hope that by learning how to control this signal, they can find new treatments for diseases such as osteoporosis.

Building and Re-Building Bone

Surprisingly, bone is a very dynamic tissue, constantly breaking down and rebuilding itself over time. Bone tissue is built by cells called osteoblasts, and is broken down by cells called osteoclasts. Bone density increases during childhood and adolescence, reaching a peak at about 25 years of age. After about 10 years at peak density, bones begin to break down more than they build up. The result is thinning and weakening of the bones with age. Maximizing peak bone density by getting sufficient dietary calcium during adolescence is crucial to future bone health, because the stronger bones are at their peak, the better they can withstand aging. Once the age for maximizing bone density is past, bones cannot be built up to peak density. When bones break down too much more than they are built up, osteoporosis, or porous bones, can occur. Osteoporosis can lead to extremely fragile bones, resulting in fractures from minor falls, injuries, or even sneezing. Fractures can occur in bones that do not normally break in healthy adults, including the hip bone, femur (leg bone), or spine.

In the United States, about 10 million adults have osteoporosis, and another 34 million have low bone mass, placing them at risk. Eighty percent of people with osteoporosis are women, and changing hormones associated with menopause greatly accelerate bone loss. Current osteoporosis treatments work by slowing down the action of the osteoclasts, thereby slowing bone destruction. However, the only treatment that directly influences new bone formation is parathyroid hormone (Forteo), a treatment reserved only for the most severe cases of osteoporosis because of its side effects and cost. Osteoporosis is currently an important public health concern, with total costs resulting from fractures in 2005 reaching $19 billion. This amount is expected to increase by 50% by the year 2025, due to the increase in expected lifespan and aging of the ?Baby Boomer? generation. Therefore, improved treatments for osteoporosis are desperately needed.

The Gut-Bone Connection

The important discovery about the link between the gut and bone was made somewhat serendipitously. Researchers were looking at the role of a protein, LDL receptor-related protein 5 (LRP5), in bone regulation. Previously, there were several bone diseases in humans that were known to be caused by mutations in the gene for LRP5. Mutations in LRP5 that cause LRP5 to be inactive lead to a form of osteoporosis that begins in childhood. On the other hand, mutations in LRP5 that cause LRP5 to be over-active lead to very dense bones that are more difficult than normal to break. It was thought that LRP5 acted in the bone, but Dr. Karsenty and colleagues found that if they made LRP5 inactive only in the bones of mice, there was no effect on bone density. However, if they made LRP5 inactive only in the gut, the mice developed osteoporosis, just like human patients. Similarly, if they made LRP5 over-active in the gut, but not in the bone, mice developed extra-dense bones. The bone cells from the mice with mutated LRP5 could grow normally in the laboratory, suggesting the bone cells themselves were healthy, and were responding to something in their environment that told them not to grow. Together, these results told researchers that LRP5 in the gut was influencing something else that was released into the blood circulation to reach the bone tissue. The surprising answer turned out the be serotonin, a chemical well-studied in the brain, but mysterious in the gut.

A Brain Chemical ? In Your Gut?

Serotonin is a chemical used by cells in the brain to communicate with each other and influence the rest of the body. It helps regulate many complex processes, including mood, appetite, body temperature, and aggression. Many anti-depressants are selective serotonin reuptake inhibitors (SSRIs), and work by increasing the level of serotonin in the brain. However, 95% of all serotonin is made in the gut, not in the brain. The gut serotonin is released into the bloodstream, but cannot reach the brain because it is blocked by a special membrane called the blood-brain barrier. Until now, scientists have been unsure what the role of this gut serotonin could be.

Serotonin and Bone Formation

Dr. Karsenty and colleagues found that LRP5 normally blocks a necessary step in the process of making serotonin in the gut. Without LRP5, serotonin levels in the blood become much higher than normal, in both the mice that the researchers were studying, and in human patients with inactive LRP5 mutations that cause osteoporosis. Conversely, in mice and humans with over-active LRP5 and extra-dense bones, serotonin levels are decreased. Researchers tested the idea that serotonin influences bone formation by applying serotonin to bone cells in the laboratory. They found that serotonin prevented the replication of osteoblasts, the cells that help rebuild bone. Next, researchers were able to manipulate the amount of gut serotonin in the mice to alter the density of the bones. They found that if mice with the inactive LRP5 mutation were given a drug that prevents serotonin synthesis in the gut, the mice had normal bone density. The same drug also prevented osteoporosis in female mice undergoing artificial ?menopause? brought on by removing their ovaries, a procedure that normally induces osteoporosis in mice. Finally, researchers were able to lower serotonin levels and improve bone density in mice with the inactive LRP5 mutation by feeding them a diet low in tryptophan, a precursor of serotonin. Tryptophan is a building block of proteins, and is found in high amounts in foods such as poultry (including turkey), red meat, eggs, fish, milk, and peanuts. These results suggest that levels of serotonin can be altered to improve bone density through the use of drugs or diet. Importantly, altering the levels of gut serotonin in the mice did not alter the levels of serotonin in the brain.

Looking Towards the Future

Scientists are optimistic that this new understanding of the dynamics of bone regulation could lead to potentially new and innovative treatments for osteoporosis. Decreasing levels of serotonin increased the rate at which osteoblasts built up the bone, which is an important distinction from current treatments that only slow bone destruction. With this new focus for research efforts, the future of osteoporosis treatments is looking brighter already.

–Stephanie Courchesne, Harvard Medical School

For More Information:

More information from the New York Times:
< http://www.nytimes.com/2008/11/27/health/research/27bone.html >

Health News article:
< http://www.healthnews.com/family-health/womens-health/groundbreaking-osteoporosis-breakthrough-2205.html >

EurekAlert article:
< http://www.eurekalert.org/pub_releases/2008-11/cumc-itg111908.php >

Osteoporosis Facts from the National Osteoporosis Foundation:
< http://www.nof.org/ >

Primary Literature:

Yadav VK, Ryu J-H, Suda N, Tanaka KF, Gingrich JA, Schutz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, and Karsenty (2008) Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell, 135, 825-837.

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