Bone formation goes with the gut, study finds

November 26, 2008

When it comes to remodeling our bones--an ongoing process of break down and renewal that goes on throughout adulthood--researchers have new evidence that our guts play a surprisingly important role. The findings point toward novel methods for increasing bone mass in patients with diseases characterized by impaired bone formation, including postmenopausal osteoporosis, according to the report in the November 26th issue of the journal Cell, a Cell Press publication.

" This is totally new," said Gerard Karsenty of Columbia University. "We had no clue that the gut had control over bone, and in such a powerful manner."

Too much serotonin released by the gut leads to a decline in bone mass; too little and bones bulk up beyond what is normal, their study shows. While serotonin is most familiar for its effects on the brain, 95 percent of all serotonin in the body is actually produced by the gut, Karsenty explained. Just what that serotonin did, however, had remained a matter of considerable debate.

The current study was aimed at clearing up the role of a gene that encodes LDL-receptor related protein 5 (LRP5), one of the most intensely studied regulators of bone remodeling. Patients with a genetic mutation that leads to a loss of that protein's function have a rare disease known as osteoporosis pseudoglioma (OPPG), characterized by a severe decline in bone formation and other symptoms. Other, presumably activating, mutations in LRP5 cause high bone mass syndrome. "That different mutations in this gene cause two bone diseases of opposite nature underscores the critical importance in the regulation of bone formation of the pathway or pathways controlled by Lrp5," the researchers said.

Earlier studies had suggested LRP5 might operate on bone through one developmental pathway, but Karsenty's team wasn't convinced that was the whole story. They've now confirmed that hunch.

They find that the bones of mice lacking Lrp5 show a rise in the activity of an enzyme called tryptophan hydroxylase 1 (Tph1). Tph1 limits the rate of serotonin production in the gut from the amino acid tryptophan. (Amino acids are the building blocks of proteins.) In other words, mice without Lrp5 have too much Tph1, leading them to overproduce gut serotonin.

Further study showed that decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and that gut- but not bone-specific Lrp5 inactivation decreases bone formation. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents bone loss in mice who have had their ovaries removed, a condition that mimics menopause.

Although the findings were made in mice, Karsenty says they have direct application to understanding bone remodeling in humans, and to the development of treatments designed to increase bone mass.

" This is not a mouse story," Karsenty said. "From the beginning it was a human story that we've now worked out in the mouse."

The findings suggest that OPPG and high bone mass syndrome are actually more gut- than bone-originating diseases. It also provides an explanation for another observation: that patients with autism who have high blood serotonin levels often have osteoporosis. Patients taking synthetic serotonin reuptake inhibitors (SSRIs) chronically, a class of antidepressant drugs that increase extracellular serotonin concentration, can also have reduced bone mass, the researchers noted. They emphasized however, that it's too soon to say whether this new connection between gut serotonin and bone will explain that side effect of the drugs or not.

So, given the gut's newfound pull over bone, might diet play a role?

While the researchers did show in mice that a diet low in the tryptophan--the raw ingredient for serotonin's manufacture--can have an effect on bone mass, at least in the Lrp5-deficient mice, Karsenty thinks that serotonin inhibiting drugs are a more likely method than diet for building bone mass in people. Coincidentally, however, one of the highest sources of tryptophan is the Thanksgiving turkey.
The researchers include Vijay K. Yadav, Columbia University, New York, NY; Je-Hwang Ryu, Columbia University, New York, NY; Nina Suda, Columbia University, New York, NY; Kenji F. Tanaka, Columbia University, New York, NY; Jay A. Gingrich, Columbia University, New York, NY; Gunther Schutz, German Cancer Research Center, Heidelberg, Germany; Francis H. Glorieux, Shriners Hospital for Children, McGill University, Montreal, Canada; Cherie Y. Chiang, University of Melbourne, Heidelberg, Australia; Jeffrey D. Zajac, University of Melbourne, Heidelberg, Australia; Karl L. Insogna, Yale School of Medicine, New Haven, CT; J. John Mann, Columbia University, New York, NY; Rene Hen, Columbia University, New York, NY; Patricia Ducy, Columbia University, New York, NY, and Gerard Karsenty, Columbia University, New York, NY.

Cell Press

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