Serotonin_ what the gut feeds the bones _ science news

Serotonin: What The Gut Feeds The Bones / Science News http://www.sciencenews.org/view/feature/id/43994 SEROTONIN: WHAT THE GUT FEEDS THE BONES
Chemical messenger plays a surprising role in determining the
strength of the skeleton
A SURPRISE ROLE| Serotonin is produced in the small intestine (seenright, center in this X-ray image; stomach is upper right) and then carriedinto bone, where it affects bone formation and density.
The hip bone is connected to the backbone. The backbone is connected to theneck bone. And lately, scientists have begun to think that all dem bones maybe connected to the intestine — at least by biochemical signals. If the currentevidence holds up, it means that a chemical better known for influencing thebrain may also corrode the internal structure of the skeleton.
Such is the state of research into bone biology: “The more we understand, themore complex it gets,” says Clifford Rosen of the Maine Medical CenterResearch Institute in Scarborough. Rosen is one of a growing number ofresearchers who think that the brain, intestine and skeleton are conducting anongoing biochemical negotiation that affects the ebb and flow of tissue buildinginside bones. One of the chief currencies appears to be serotonin, aneurotransmitter most famous for its role in depression.
The idea that serotonin might be bad news for bones came as a surprisealmost a decade ago. And the notion that the intestine hosts a serotonin-bonecommand center — first described last fall — was more surprising still. “Itʼsthrown the field into a bit of an uproar,” says Michael Bliziotes of OregonHealth & Science University in Portland.
By eavesdropping on the crosstalk between the intestine and skeleton,researchers hope to find much-needed ways to help protect bones into oldage. More than 300,000 elderly Americans suffer hip fractures each year; onein five die within a year from complications of the injury. Bone-strengthening http://www.sciencenews.org/view/feature/id/43994/title/Serotonin_What_the_gut_feeds_the_bones Serotonin: What The Gut Feeds The Bones / Science News in five die within a year from complications of the injury. Bone-strengtheningmedications have been hard to come by, largely because bone issimultaneously one of the most simple and most convoluted structures in thebody — brilliant and straightforward in engineering, yet owing its constructionto an elaborate relationship with internal organs.
Itʼs easy to perceive bones as dense and dead. But on the inside, bones arenot hard like blocks of wood, but airy, like sponges. The internal, honeycomb-like scaffolding allows bones to be sturdy without leaving them too heavy.
Strength isnʼt determined by density but by the makeup of the matrix within (inthe same way a china plate is denser than a plastic one but less likely tosurvive a drop on the floor).
Neither are bones dead. Throughout life, bones are constantly remodelingthemselves, constructing new tissue in some places, clearing out old bone inothers. As with hair or skin, worn bone 
tissue is constantly replaced with newin what is called bone turnover. Bones generally reach their maximum strengthin early adulthood, after which they gradually wear away. After decades oferosion, bone density sometimes dips low enough to qualify as osteoporosis.
That disorder occurs largely because, as people age, cells that secrete newbone, called osteoblasts, donʼt work as robustly as osteoclasts, cells thatresorb or break down bone, especially in postmenopausal women. Mosttreatments for osteoporosis slow the loss of bone; the one drug that can buildbone costs thousands of dollars a year per patient and isnʼt prescribed as along-term option.
Nutrients and hormones — including vitamin D, calcium and estrogen — arecrucial to maintaining a favorable rate of bone turnover. Strength training alsotips the balance toward osteoblasts. These aspects of bone biology are clear.
But scientists acknowledge that much of the skeleton-building story remains amystery.
Unexpected connections
The link between serotonin and bones turned up, as scientific discoveries oftendo, when researchers were looking for something else altogether. In 2000,scientists at Duke University in Durham, N.C., were conducting studies onsubstance abuse with mice specifically bred to lack certain brain moleculescalled dopamine transporters, which interact with the neurotransmitterdopamine. The scientists noticed that the mice seemed to have extraordinarilybrittle bones. Bliziotes, an endocrinologist who had been collaborating with theDuke team, began to search for a biochemical explanation.
http://www.sciencenews.org/view/feature/id/43994/title/Serotonin_What_the_gut_feeds_the_bones Serotonin: What The Gut Feeds The Bones / Science News THAT GUT FEELING CREEPS INTO YOUR BONES | Serotonin may be best known for its role in the brain,where it helps regulate mood, learning and sleep. But most of the bodyʼsserotonin is made in the gut and never crosses the blood-brain barrier.
Eating a meal stimulates the Tph1 enzyme, which makes serotonin in thegut. The signaling molecule Lrp5 can block serotonin production, helping toregulate serotonin levels. Blood platelets move serotonin throughout thebody and into bone. Because it binds to serotonin receptor 1b, theneurotransmitter in excess can hinder the formation of new bone cells calledosteoblasts. This may lead to lower bone density by upsetting the normalbalance between bone formation and loss. In people, genetic mutations inthe Lrp5 gene have been linked to bone density problems.
Graphic by C. Rosen modified and reprinted with permission from the NewEngland Journal of Medicine, 2009; Brain image: N-L/Istockphoto Although they went searching for dopamine transporters in the bones of normalmice, the researchers were astonished to instead find transporter molecules forserotonin, Bliziotes and his colleagues reported in the journal Bone in 2001.
And the serotonin transporter molecules turned up in all types of bone cells —osteoblasts, osteoclasts and, later work showed, osteocytes, cells derived fromosteoblasts. That same year, a Dutch research team studying chicken embryosalso discovered a role for the neurotransmitter in bone. “Before 2001, it wasnʼtknown that serotonin had any involvement in bone,” Bliziotes says.
In the brain, low levels of available serotonin are thought to contribute todepression. Indeed, the most famous antidepressant in the medicine cabinet —Prozac — works to boost the supply of serotonin available in brain synapses,junctures where neurons communicate. So what was serotonin doing inbones? Apparently, making them weaker: Serotonin seems to interfere with theproduction of the bone-forming osteoblasts. Following the discovery of aserotonin connection to bones, Bliziotes and others began to worry about themore than 8 percent of U.S. adults who take Prozac and related drugs calledselective serotonin reuptake inhibitors, or SSRIs, to amplify serotonin. In 2007in the Archives of Internal Medicine, Bliziotes and his colleagues described astudy of almost 6,000 older men involved in an osteoporosis investigation. Mentaking SSRIs had lower average bone density than those not on the drugs. Arelated study of postmenopausal women found that bone density declined inthose taking SSRIs twice as fast as it did in other women.
“I think the major question right now is — if depressed people are going to betreated with SSRIs, are we subjecting them to risk of fracture?” says Bliziotes.
The issue is still under investigation, largely because the studies are difficult tointerpret. Among people taking SSRIs, Bliziotes says, “most of them are goingto have been put on SSRIs for symptoms of depression. Depression alone hasbeen associated with lower bone density.” And people with depression mayhave weaker bones not from their own physiology but because of lifestylechanges that can accompany the condition, including poor nutrition and lowlevels of exercise. “We havenʼt done randomized trials,” Bliziotes notes.
http://www.sciencenews.org/view/feature/id/43994/title/Serotonin_What_the_gut_feeds_the_bones Serotonin: What The Gut Feeds The Bones / Science News levels of exercise. “We havenʼt done randomized trials,” Bliziotes notes.
To further investigate the role of serotonin, researchers have looked to bonetissue itself to characterize the neurotransmitterʼs influence over bone cells.
These studies have led to a family of proteins called Wnt. (The name comesfrom a combination of two genes first discovered in fruit flies — wingless andINT — and is pronounced “wint.”) Wnt proteins have so many functions that abook about them takes up two volumes. Medical researchers have an intenseinterest in Wnts because the molecules appear to be involved in cancer, heartdisease, obesity and many other conditions. But Wnts also orchestrate basicdevelopment and maintenance of body parts.
The fruit fly Wnt proteins have human counterparts, including, of specialinterest to bone researchers, the signaling protein Lrp5. About a decade ago,researchers found that mice with a mutated form of the gene for Lrp5 had lowbone density. In people, mutations in this gene can lead to two distinct effectson bone. One is osteoporosis-pseudoglioma, a rare syndrome that affectschildren, giving them bones often too fragile even for walking, along with visionproblems early in life. A different mutation in the gene produces a condition atthe other end of the clinical spectrum: high bone mass syndrome, renderingbones unusually dense and protected against osteoporosis. Looking at theeffects of these mutations in people, it became clear that Lrp5 had the powerto make or break bone.
“Since the discovery of Lrp5, there has been a tremendous effort to study howit works,” says Gerard Karsenty of Columbia University Medical Center. Untillast year, most researchers assumed that whatever the role of Lrp5, itsimportance started and ended in the skeleton. Then in November, Karsentyand his colleagues published a paper in Cell that was, in bone researchcircles, jaw dropping: In experiments with mice, he demonstrated that Lrp5affects the production of serotonin in the duodenum, the segment of the smallintestine where most digestion of food occurs (SN Online: 11/26/08).
Despite the neurotransmitterʼs fame in the brain, 95 percent of the bodyʼsserotonin is made in the intestine, from the amino acid tryptophan, which is acomponent of dietary protein (and lore aside, is no more prevalent in turkeythan other meats). After a meal, the intestine turns tryptophan into serotonin,while platelets from the bloodstream ferry serotonin throughout the body. Itʼs anentirely separate circuitry from serotonin production in the brain. Serotoninmade in the brain stays in the brain, and the two different sources donʼtmingle.
Karsentyʼs experiments found that Lrp5 interferes with the production ofserotonin in the gut. To arrive at this conclusion, he and his colleagues bredmice with gene mutations known to hamper bone formation. Yet when bonecells from these mice were isolated in laboratory dishes, and thus removedfrom exposure to serotonin, they grew normally. In short, when not exposed toserotonin, the tissue appeared to be just fine. Similarly, when normal bonecells were exposed to serotonin in the laboratory, their growth slowed.
According to these experiments, the problem with bone growth seemed to lieoutside of bone cells and not in some faulty bone-building mechanism.
http://www.sciencenews.org/view/feature/id/43994/title/Serotonin_What_the_gut_feeds_the_bones Serotonin: What The Gut Feeds The Bones / Science News That led Karsentyʼs team to search for other organs that might affect boneformation. In the Cell paper, he and his colleagues reported that Lrp5 acted inthe gut, blocking a key enzyme necessary for the conversion of tryptophan toserotonin. When the intestine is awash in Lrp5, less serotonin gets produced,and bones remain stronger. Less Lrp5 means more serotonin, and weakerbones. “This study uncovers an unanticipated molecular mechanismaccounting for the Lrp5 regulation of bone formation,” the researchers wrote.
Serotoninʼs long reach
Key questions remain. Among them: How might all this knowledge one daytranslate into a medical benefit? Other, broader issues go beyond the skeleton.
Serotonin isnʼt present just in the brain, intestine and bones. It worksthroughout the body, tweaking many different systems, including thecardiovascular system and digestion. “If you turn off the main site of synthesis,what kind of bad effects are you going to have?” says Bliziotes. No one can besure until the cellular machinery is better understood.
Rosen also wonders how the brain comes into this picture. Although theserotonin in the brain and intestine never meet, evidence suggests that thebrain may have other effects on bones. Some of that influence may even actthrough the digestive system. The hormone leptin suppresses appetite but isalso implicated in the regulation of bone mass. And Rosen points to other hintsof a brain-bone connection. For example, the rate of new bone formationincreases after traumatic head injury.
Rosen isnʼt surprised that the skeleton would have a connection to the gut.
Bones are the bodyʼs biggest storehouse for calcium. Bone turnover slowsafter eating, probably to keep calcium locked in the bones, he says, andincreases during fasting. Through serotonin, the intestine may be cueing bonesto slow or to rev up turnover based on the bodyʼs need for calcium. Ultimately,he believes, scientists may find that bones have a more intimate connection toother organs than anyone first thought. “I think we have just scratched thesurface,” Rosen says.
For now, scientists are eager to learn more about serotonin and how critical arole it may have in bone structure. More than anything, says researcher FanxinLong of Washington University Medical School in St. Louis, the new findingsare a stark reminder that no organ in the body operates as its own, isolatedfiefdom. “It highlights a picture that has become more and more clear,” Longsays. “Different organs in the body talk to each other.” In a language scientistshope to one day fully understand.
That gut feeling creeps into your bones
Serotonin may be best known for its role in the brain, where it helps regulatemood, learning and sleep. But most of the bodyʼs serotonin is made in the gutand never crosses the blood-brain barrier. Eating a meal stimulates the Tph1enzyme, which makes serotonin in the gut. The signaling molecule Lrp5 canblock serotonin production, helping to regulate serotonin levels. Blood plateletsmove serotonin throughout the body and into bone. Because it binds toserotonin receptor 1b, the neurotransmitter in excess can hinder the formationof new bone cells called osteoblasts. This may lead to lower bone density by http://www.sciencenews.org/view/feature/id/43994/title/Serotonin_What_the_gut_feeds_the_bones Serotonin: What The Gut Feeds The Bones / Science News of new bone cells called osteoblasts. This may lead to lower bone density byupsetting the normal balance between bone formation and loss. In people,genetic mutations in the Lrp5 gene have been linked to bone density problems.
Laura Beil is a freelance science writer in Cedar Hill, Texas. http://www.sciencenews.org/view/feature/id/43994/title/Serotonin_What_the_gut_feeds_the_bones

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