Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

It Takes Guts to Build Bone

01.12.2008
Bone growth is controlled in the gut through serotonin, the same naturally present chemical used by the brain to influence mood, appetite and sleep, according to a new discovery from researchers at Columbia University Medical Center.

Until now, the skeleton was thought to control bone growth, and serotonin was primarily known as a neurotransmitter acting in the brain. This new insight could transform how osteoporosis is treated in the future by giving doctors a way to increase bone mass, not just slow its loss. Findings are reported in the Nov. 26, 2008 issue of Cell.

Researchers have known that 95 percent of the body’s serotonin is produced by a part of the gastrointestinal tract known as the duodenum, where it was presumed to be involved in digestion. The brain is where the remaining five percent of the body’s serotonin is produced.

The Columbia research group, led by Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University College of Physicians and Surgeons, had originally set out to elucidate two rare human diseases affecting bone that are both caused by a mutation in a gene called Lrp5. To their surprise, Dr. Karsenty and his team found that Lrp5 regulates synthesis of serotonin in the gut, and that by turning on or turning off the production of this chemical within the gut, they could control bone formation. Specifically, they found that serotonin tells cells in the skeleton to slow production of new bone. By turning off the intestine’s release of serotonin, the team was able to prevent osteoporosis in mice undergoing menopause.

“This proof-of-principle paper shows, to our amazement, that bone formation is regulated to a significant extent by the gut! Through our observations of two rare and severe forms of osteoporosis, one that causes drastic bone loss and one that causes extremely high bone mass, we were able to see clearly what happens with over-production or under-production of serotonin,” said Dr. Karsenty. “Our hope is that this novel discovery will inform the development of new therapies for the millions of people with osteoporosis.”

Challenging Fundamental Understanding of Bone Formation

Far from being inert, bone constantly undergoes renovation, with some cells responsible for removing old material and other cells responsible for creating new bone. In humans, after age 20, the balance between bone formation and breakdown tips toward breakdown, and bone mass starts to decline. In women, the rate of decline increases after menopause, when estrogen levels drop and cells that tear down old bone become overactive. Osteoporosis is a disease in which bones become fragile and porous, increasing the risk of breaks. It is diagnosed when bone mass drops below a certain level.

This discovery that intestinal serotonin is central to bone formation will likely challenge previously held beliefs among researchers in the field, who have thought for years that the majority of hormones that control bone mass had been identified.

A crucial clue uncovered in Dr. Karsenty’s lab turned his attention to the small intestine. His research team found that the gene Lrp5, which had been previously linked to a rare form of osteoporosis, controls the production of serotonin in the gut, and that serotonin is an inhibitor of bone formation. Indeed, by inactivating Lrp5 in the small intestine of mice and thereby turning on the production of serotonin, bone mass decreased. While in contrast, the deletion of the same gene in the bone cells of mice, on the other hand, had no effect on bone mass.

“The findings demonstrate without a doubt that serotonin from the gut is acting as a hormone to regulate bone mass,” said Dr. Karsenty. “As an endocrinologist, I have spent a large part of my career investigating the interplay between energy metabolisms and bone mass. This demonstration of the vital function of bone proliferation stemming from the gut gives pause to those in my field who perhaps have not given the gut its due examination or the credit it deserves for how much it controls in the body, and that includes me.”

Though all the experiments were conducted in mice, the findings apply to humans, according to Dr. Karsenty, since this work was prompted by the elucidation of the two human genetic bone diseases. Indeed, Dr. Karsenty’s group verified that circulating serotonin levels were abnormal in human patients with both diseases.

Implications for the Treatment of Osteoporosis

Most osteoporosis drugs, including those currently under clinical investigation, do not generate new bone but prevent the breakdown of old bone. Only one drug currently on the market can generate new bone, but due to reports that it may increase the risk of bone cancer, its use is restricted for short-term use in women with severe osteoporosis.

“This lack of bone promoting drugs is a major concern because osteoporosis 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.”

Reducing serotonin release from the small intestine should be relatively simple to achieve with a drug, according to Dr. Karsenty, because the cells that produce serotonin come into direct contact with drugs that pass through the gastrointestinal tract. An inhibitor of gut-derived serotonin synthesis would not need to enter the general circulation, thereby avoiding many potential side effects.

Dr. Karsenty and his colleagues did not find any gastrointestinal problems in mice unable to produce serotonin in their guts, suggesting that a serotonin inhibitor would not produce any such side effects in humans.

This research was supported by grants from the March of Dimes Foundation and the National Institutes of Health.

Co-authors on this paper include Vijay K. Yadav, Je-Hwang Ryu, and Nina Suda from the Department of Genetics and Development at Columbia University Medical Center (CUMC); Kenji Tanaka and Rene Hen, Department of Pharmacology (CUMC); Jay A. Gingrich, Department of Psychiatry-Developmental Psychobiology (CUMC); Gunther Schutz, Department of Molecular Biology of the Cell, German Research Center, Heidelberg Germany; Francis Glorieux, Shriners Hospital for Children, McGill University, Montreal, Canada; Cherie Y. Chiang and Jeffrey D. Zajac, Department of Medicine, University of Melbourne, Heidelberg, Australia; Karl L. Insogna, Department of Internal Medicine, Yale School of Medicine; J. John Mann, Department of Psychiatry (CUMC), and Patricia Ducy, Department of Pathology (CUMC).

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future health care leaders at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians & Surgeons was the first in the country to grant the M.D. degree. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.

Elizabeth Streich | Newswise Science News
Further information:
http://www.columbia.edu
http://www.cumc.columbia.edu

More articles from Life Sciences:

nachricht Plant mothers talk to their embryos via the hormone auxin
17.07.2018 | Institute of Science and Technology Austria

nachricht Barium ruthenate: A high-yield, easy-to-handle perovskite catalyst for the oxidation of sulfides
16.07.2018 | Tokyo Institute of Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Subaru Telescope helps pinpoint origin of ultra-high energy neutrino

16.07.2018 | Physics and Astronomy

Barium ruthenate: A high-yield, easy-to-handle perovskite catalyst for the oxidation of sulfides

16.07.2018 | Life Sciences

New research calculates capacity of North American forests to sequester carbon

16.07.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>