Wednesday, February 10, 2010

Inhibition of serotonin synthesis in gut - a new way of treating osteoporosis ?

A crucial clue uncovered in Dr. Karsenty’s lab turned his attention to the small intestine, wherein his research team found that the gene Lrp5, (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. 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. As per the claim by the researcher, these findings demonstrate that serotonin from the gut is acting as a hormone to regulate bone mass (1). 

Most osteoporosis drugs, including those currently under clinical investigation  do not generate new bone but prevent the breakdown of old bone and the only drug currently in  the market which can generate new bone   has its limited application (due to its reported increased risk of bone cancer,is restricted for short-term and  that too in women with severe osteoporosis). Researchers  read about an investigational drug, known as LP533401  which is able to inhibit serotonin in the gut they synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1)  the initial enzyme in GDS biosynthesis.

Results demonstrated that osteoporosis was prevented from developing, or when already present, could be fully cured (in mice). Interestingly  levels of serotonin were normal in the brain, which indicated that the compound did not enter the general circulation and was unable to cross the blood-brain barrier, 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. The authors conclude that these results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

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