Hope for Osteoporosis

Serotonin in Gut Linked to Bone Formation

By Michael Smith, North American Correspondent, MedPage Today
Published: November 26, 2008
Reviewed by
Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

 Serotonin in the brain is associated with mood and cognitive functions, but 95% of the body’s supply of the molecule is produced in the gut and its function has not been understood.  The compound plays a key role in regulating bone formation, opening the possibility of novel treatments for diseases such as osteoporosis.

NEW YORK, Nov. 26 — That Thanksgiving turkey may be bad for your bones.
That’s one of the implications of a study that — for the first time — links the gut to bone formation, according to Gerard Karsenty, M.D., Ph.D., of the Columbia University College of Physicians and Surgeons, and colleagues.
The research, conducted mainly in mice, links serotonin produced in the duodenum to the proliferation of osteoblasts, the cells that create new bone, Dr. Karsenty and colleagues reported in the Nov. 26 issue of Cell.
"This is totally new," Dr. Karsenty said. "We had no clue that the gut had control over bone, and in such a powerful manner."

The findings open up the possibility of controlling such diseases as osteoporosis either by a diet low in tryptophan — the raw material for serotonin synthesis — or by inhibiting the serotonin-osteoblast interaction with medications.

If diet turns out to be a possible approach, the turkey may have to go –it’s one of the best dietary sources of tryptophan.

Until these experiments, Dr. Karsenty said, the function of gut-associated serotonin was not known.

"The findings demonstrate without a doubt that serotonin from the gut is acting as a hormone to regulate bone mass," he said.

But the discovery was accidental. The researchers were investigating the role of a protein known as LDL-receptor related protein 5 (or LRP5), which causes osteoporosis pseudoglioma when mutations lead to a loss of function.

Other mutations in LPR5, which presumably cause overactivity (gain-of-function mutations), are associated with diseases characterized by high bone mass, the researchers noted.

The first hint of a link to serotonin came when they noted that a key player in the molecule’s synthesis — the enzyme tryptophan hydroxylase 1 (or Tph1) — is highly overexpressed in the duodenum of mice lacking LPR5.

Tph1 is the enzyme that limits the rate at which serotonin is produced in the gut. Indeed, 95% of the body’s serotonin is produced in the gut; because it does not cross the blood-brain barrier, a second enzyme, Tph2, is responsible for serotonin in the brain.

In mice lacking LRP5, levels of Tph1 are normal at birth and begin to show significant increases (at P0.01) compared to wild-type animals at two weeks of age.

The low bone mass syndrome in those animals begins to appear two weeks later.

In parallel, serum serotonin levels also increase as the animals age, the researchers noted.

Interestingly, the researchers noted, in an earlier case-control analysis of three patients with osteoporosis pseudoglioma, serum serotonin levels were four- to five-fold higher than in six age-matched controls.

In an in vitro experiment, the researchers found that serotonin inhibits osteoblast proliferation, so they fed mice a diet with 75% less tryptophan than normal.

In mice lacking LPR5 — and therefore prone to low bone mass — the diet decreased circulating serotonin levels eight- to 10-fold (without affecting serotonin in the brain) and normalized both bone mass and bone formation parameters.

A similar experiment, using a compound that blocks serotonin synthesis, had nearly identical results.

The researchers also found that only one of the three serotonin receptors on osteoblasts (a molecule dubbed Htr1b) is involved in the process — blocking the other two had no effect on bone mass, while blocking Htr1b increased the number of osteoblasts, bone mass, and the bone formation rate.

In a final experiment, they engineered mice lacking the gene for Tph1 and removed the ovaries from female animals at six weeks of age. At three months, bone resorption had increased, but the animals had not developed low bone mass because they were still building new bone.

That experiment in particular holds out clinical promise, Dr. Karsenty said.

"Osteoporosis is often diagnosed when the damage to bone is already significant and fracture risk is already too high," he said. "We need something to build bone, not just prevent or repair its loss."

The cells that produce serotonin come in contact with drugs that pass through the gastrointestinal tract, he said, so reducing gut-associated serotonin should be relatively simple to achieve with a drug.

Dr. Karsenty said he thinks there should be few side effects of such a drug, since patients with high bone mass often have circulating serotonin levels as much as 50% higher than normal without other symptoms.

He added that he sees no theoretical obstacles to finding medications that modulate the body’s serotonin. "If we can do it in the brain," he said, "we can do it in the body."

The study was supported by the March of Dimes Foundation and the NIH. The researchers reported no conflicts.

Primary source: Cell
Source reference:
Yadav VK, et al "Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum" Cell 2008; 135, 825-837.
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