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.

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Ceregene's Phase 2 trial was a double-blind, controlled clinical trial that completed enrollment of 58 patients with advanced Parkinson's disease in November 2007. This study was launched after successful execution of an extensive nonclinical program and preliminary evidence of safety and efficacy in advanced Parkinson's patients via an open-label Phase 1 trial in 12 patients. Patients in the Phase 2 trial were enrolled across nine leading academic medical centers in the United States, with two thirds of patients receiving CERE-120 and one third enrolled into a control group. Patients received a single administration of CERE-120 via stereotactic neurosurgery to deliver the drug into the putamen region of the brain and were followed for 12 months for safety and efficacy.

CERE-120 is composed of an adeno-associated virus (AAV) vector carrying the gene for neurturin (NTN), a naturally occurring protein known to repair

damaged and dying dopamine-secreting neurons, keeping them alive and restoring normal function. NTN is a member of the same protein family as glial cell-derived neurotrophic factor (GDNF). The two molecules have similar pharmacological properties, and both have been shown to benefit the midbrain dopamine neurons that degenerate in Parkinson's disease and are responsible for the major motor impairments. CERE-120 is delivered by stereotactic injection to the affected area of the brain, providing stable, long-lasting expression of NTN in a highly targeted fashion. Genzyme Corporation has licensed the ex-North American rights for the development and commercialization of CERE-120 from Ceregene, an agreement that was announced in June 2007. Ceregene gratefully acknowledges the financial support received from the Michael J. Fox Foundation for Parkinson's Research to help defray some of the costs of the CERE-120 Phase 1 and Phase 2 clinical trials.

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